Modified alginates for anti-fibrotic materials and applications

ABSTRACT

Covalently modified alginate polymers, possessing enhanced biocompatibility and tailored physiochemical properties, as well as methods of making and use thereof, are disclosed herein. The covalently modified alginates are useful as a matrix for coating of any material where reduced fibrosis is desired, such as encapsulated cells for transplantation and medical devices implanted or used in the body.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of PCT Application No.PCT/US2016/059967, filed Nov. 1, 2016, which claims the benefit of andpriority to U.S. Provisional Application No. 62/249,335, filed Nov. 1,2015, the entire contents of which is incorporated by reference in itsentirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with government support under Grants EB000244,EB000351, DE013023 and CA151884 awarded by the National Institutes ofHealth (NIH) and Grant W81XWH-13-1-0215 awarded by the Department ofDefense (DOD). The government has certain rights in the invention.

REFERENCE TO SEQUENCE LISTING

The Sequence Listing submitted as a text file named“MIT_16906_CIP_ST25.txt,” created on Nov. 1, 2016, and having a size of4,994 bytes is hereby incorporated by reference pursuant to 37 C.F.R. §1.52(e)(5).

FIELD OF THE INVENTION

The present invention relates to the use of alginates, chemicallymodified to enhance their properties, e.g., biocompatibility andanti-fibrotic properties; to their use to coat or encapsulate materials,products, and devices, such as cells, implants, and medical devices; andto methods of treating diseases or disorders, including diabetes, byimplantation of the modified alginates and materials coated orencapsulated with the modified alginates.

BACKGROUND OF THE INVENTION

The foreign body response is an immune-mediated reaction that impactsthe fidelity of implanted biomedical devices (Anderson et al., Semin.Immunol. 20:86-100 (2008); Langer, Adv. Mater. 21:3235-3236 (2009);Ward, J. Diabetes Sci. Technol. Online 2:768-777 (2008); Harding &Reynolds, Trends Biotechnol. 32:140-146 (2014)). Macrophage recognitionof biomaterial surfaces in these devices initiate a cascade ofinflammatory events that result in the fibrous and collagenousencapsulation of these foreign materials (Anderson et al. (2008); Ward(2008); Harding & Reynolds (2014); Grainger, Nat. Biotechnol. 31:507-509(2013); Williams, Biomaterials 29:2941-2953 (2008)). This encapsulation,over time, often leads to device failure and can result in discomfortfor the recipient (Anderson et al. (2008); Harding & Reynolds (2014);Williams (2008)). These adverse outcomes emphasize the critical need forbiomaterials that do not elicit foreign body responses to overcome thiskey challenge to long-term biomedical device function.

The foreign body response to implanted biomaterials is the culminationof inflammatory events and wound-healing processes resulting in implantencapsulation (Anderson et al. (2008)). The final pathological productof this response is fibrosis, which is characterized by the accumulationof excessive extracellular matrix at sites of inflammation and is a keyobstacle for implantable medical devices as the cellular and collagenousdeposition isolate the device from the host (Anderson et al. (2008);Wick et al., Annu. Rev. Immunol. 31:107-135 (2013); Wynn & Ramalingam.Nat. Med. 18:1028-1040 (2012)). This device isolation can interfere withsensing of the host environment, lead to painful tissue distortion, cutoff nourishment (for implants containing living, cellular components),and ultimately lead to device failure. Materials commonly used formedical device manufacture today elicit a foreign body response thatresults in fibrous encapsulation of the implanted material (Langer(2009); Ward (2008); Harding & Reynolds (2014); Williams (2008); Zhanget al., Nat. Biotechnol. 31:553-556 (2013)). Overcoming the foreign bodyresponse to implanted devices could pave the way for implementing newmedical advances, making the development of materials with bothanti-inflammatory and anti-fibrotic properties a critical medical need(Anderson et al. (2008); Langer (2009); Harding & Reynolds (2014)).

Macrophages are a key component of material recognition and activelyadhere to the surface of foreign objects (Anderson et al. (2008); Ward(2008); Grainger, Nat. Biotechnol. 31:507-509 (2013); Sussman et al.,Ann. Biomed. Eng. 1-9 (2013) (doi:10.1007/s10439-013-0933-0)). Objectstoo large for macrophage phagocytosis initiate processes that result inthe fusion of macrophages into foreign-body giant cells. Thesemulti-nucleated bodies amplify the immune response by secretingcytokines and chemokines that result in the recruitment of fibroblaststhat actively deposit matrix to isolate the foreign material (Andersonet al. (2008); Ward (2008); Rodriguez et al., J. Biomed. Mater. Res. A89:152-159 (2009); Hetrick et al., Biomaterials 28:4571-4580 (2007)).This response has been described for materials of both natural andsynthetic origins that encompass a wide range of physicochemicalproperties, including alginate, chitosan, dextran, collagen, hyaluronan,poly(ethylene glycol) (PEG), poly(methyl methacrylate) (PMMA),poly(2-hydroxyethyl methacrylate) (PHEMA), polyurethane, polyethylene,silicone rubber, Teflon, gold, titanium, silica, and alumina (Ward(2008); Ratner, J. Controlled Release 78:211-218 (2002)).

The transplantation of hormone- or protein-secreting cells fromgenetically non-identical members of the same species (i.e.allotransplantation) or from other species (i.e. xenotransplantion) is apromising strategy for the treatment of many diseases and disorders.Using alginate microcapsules to provide immunoisolation, hormone- orprotein-secreting cells can be transplanted into a patient without theneed for extensive treatment with immunosuppressant drugs. Thisprinciple has been successfully demonstrated by the transplantation ofalginate-encapsulated pancreatic β-cells in diabetic rat models (Lim, F,and Sun, A. M. Science. 210, 908-910 (1980)). Methods of encapsulatingbiological material in alginate gels are described, for example, in U.S.Pat. No. 4,352,883 to Lim. In the Lim process, an aqueous solutioncontaining the biological materials to be encapsulated is suspended in asolution of a water soluble polymer. The suspension is formed intodroplets which are configured into discrete microcapsules by contactwith multivalent cations such as Ca²⁺. The surface of the microcapsulesis subsequently crosslinked with polyamino acids, forming asemipermeable membrane around the encapsulated materials.

The Lim method employs conditions which are mild enough to encapsulatecells without adversely affecting their subsequent survival andfunction. The resulting alginate microcapsules are semipermeable,possessing sufficient porosity to permit nutrients, waste, and thehormones and/or proteins secreted from encapsulated cells to diffusefreely into and out of the microcapsules, and, when implanted into ananimal host, the alginate microcapsules effectively isolate theencapsulated cells from the host's immune system. See also U.S. Pat. No.7,807,150 to Vacanti, el al.

Many other synthetic materials have been tried, including blockcopolymers such as poly ethyleneglycol-diacrylate polymers,polyacrylates, and thermoplastic polymers, as reported by U.S. Pat. No.6,129,761 to Hubbell and by Aebischer, et al, J Biomech Eng. 1991 May113(2): 178-83. See Lesney Modern Drug Discovery 4(3), 45-46, 49, 50(2001) for review of these materials.

Since Lim first reported on the transplantation of encapsulated cells,many other have tried to create “bioreactors” for cells that couldmaintain viability of the cells in the absence of vascularization, bydiffusion of nutrients, gases and wastes through the encapsulatingmaterials, and still protect the cells from the body's immune defensesagainst foreign cells and materials. Unfortunately, efforts to translatethese therapies into human subjects have proven difficult. For example,alginate-encapsulated porcine islet cells transplanted into a humansubject suffering from Type 1 diabetes initially demonstratedsignificant improvement and required decreased insulin dosing. However,by week 49, the patient's insulin dose retuned to pre-transplant levels(Elliot, R. B. et al. Xenotransplantation. 2007; 14(2): 157-161).

In some cases, it is desirable to elicit fibrosis, for example, when thecells are implanted as a bulking material, as described in U.S. Pat. No.6,060,053 and as subsequently approved by the Food and DrugAdministration for treatment of vesicoureteral reflux.

The diminished efficacy of the implanted cells over time is the resultof fibroblastic overgrowth of the alginate capsules. The alginate gelmatrix provokes an inflammatory response upon implantation, resulting inthe encapsulation of the alginate matrix with fibrous tissue. Thefibrous tissue on the alginate capsule surface reduces the diffusion ofnutrients and oxygen to the encapsulated cells, causing them to die. Nobetter results have been obtained with the other materials.

Therefore, it is an object of the invention to provide polymers suitablefor coating products, devices, and surfaces where the polymers haveoptimized properties, e.g., greater long-term biocompatibility,following implantation of the products, devices, and surfaces.

It is also an object of the invention to provide polymers suitable forcoating products, devices, and surfaces where the polymers have lessforeign body response following implantation of the products, devices,and surfaces.

It is also an object of the invention to provide polymers suitable forencapsulation and implantation of cells where the polymers haveoptimized properties, e.g., greater long-term biocompatibility,following implantation.

It is also an object of the invention to provide polymers suitable forencapsulation and implantation of cells where the polymers have lessforeign body response following implantation.

It is also an object of the invention to provide chemically modified,ionically crosslinkable alginates with optimized properties, e.g.,improved biocompatibility and tailored physiochemical properties,including gel stability, pore size, and hydrophobicity/hydrophilicity.

It is also an object of the invention to provide chemically modified,ionically crosslinkable alginates with less foreign body response.

It is also an object of the invention to provide methods for the coatingof products, devices, and surfaces using modified alginate polymers.

It is also an object of the invention to provide methods for theencapsulation of cells using modified alginate polymers.

It is also an object of the invention to provide methods for treating adisorder or disease in a human or animal patient by transplanting orimplanting products, devices, and surfaces coated with a modifiedalginate polymer.

It is also an object of the invention to provide methods for treating adisorder or disease in a human or animal patient by transplantingexogenous biological material encapsulated in a modified alginatepolymer.

It is also an object of the invention to provide high-throughput methodsfor the characterization of modified alginate polymers.

SUMMARY OF THE INVENTION

Alginates, chemically modified to tailor their biocompatibility andphysical properties, have been developed. The modified alginatesdescribed herein provide enhanced properties relative to unmodifiedalginates. Moreover, based on the discovery that the starting materials,as well as chemically modified and reacted materials, must beexhaustively purified to remove contaminants prior to implantation toprevent encapsulation, these materials are less likely to elicit fibrouscapsule formation following implantation.

In some embodiments, modified alginates are alginate polymers thatcontain one or more covalently modified monomers defined by Formula I

wherein, in some embodiments, the modified alginate is defined byFormula Ia, Formula Ib, or a combination of Formula Ia and Formula Ib

wherein, independently for Formula I, Formula Ia, and Formula Ib,

X is oxygen, sulfur, or NR₄;

R₁ is hydrogen, or an organic grouping containing any number of carbonatoms, preferably 1-30 carbon atoms, more preferably 1-20 carbon atoms,more preferably 1-14 carbon atoms, and optionally including one or moreheteroatoms such as oxygen, sulfur, or nitrogen grouping in linear,branched, or cyclic structural formats, representative R groupings beingU₁, U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃;

Y₁ and Y₂ independently are hydrogen or —PO(OR₅)₂; or

Y₂ is absent, and Y₁. together with the two oxygen atoms to which Y₁ andY₂ are attached to form a cyclic structure as shown in Formula II,Formula IIa, Formula IIb, or a combination of Formula IIa and FormulaIIb,

wherein, independently for Formula II, Formula IIa, and Formula IIb,

R₂ and R₃ are, independently, hydrogen or an organic grouping containingany number of carbon atoms, preferably 1-30 carbon atoms, morepreferably 1-20 carbon atoms, more preferably 1-14 carbon atoms, andoptionally including one or more heteroatoms such as oxygen, sulfur, ornitrogen grouping in linear, branched, or cyclic structural formats,representative R₂ and R₃ groupings being U₁. U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄,U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃,U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferablyU₁+Q₁+Q₃; or

R₂ and R₃, together with the carbon atom to which they are attached,form a 3- to 8-membered unsubstituted or substituted carbocyclic orheterocyclic ring; and

R₄ and R₅ are, independently, hydrogen or an organic grouping containingany number of carbon atoms, preferably 1-30 carbon atoms, morepreferably 1-20 carbon atoms, more preferably 1-14 carbon atoms, andoptionally including one or more heteroatoms such as oxygen, sulfur, ornitrogen grouping in linear, branched, or cyclic structural formats,representative R₄ and R₅ groupings being U₁. U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄,U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃,U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferablyU₁+Q₁+Q₃.

In some embodiments, the modified alginates are alginate polymers thatcontain a mixture of monomers defined by Formula Ia and Formula Ib. Insome embodiments, the mixture of monomers in the modified alginate arein percent compositions (Formula Ia: Formula Ib) of 1: 99, 5: 95, 10:90, 15:85, 20:80, 25:75, 30:70, 35:65, 40:60, 45:55, 50:50, 55:45,60:40, 65:35, 70:30, 75:25, 80:20, 85:15, 90:10, 95:5, 99:1. In someembodiments the percent composition of Formula Ia and Formula Ib in themodified alginate is 1-99% Formula Ia: 1-99% Formula Ib, with theunderstanding that the sum of the percent compositions is equal to 100%.Individual integers between each of these ranges are contemplated anddisclosed.

In some embodiments, the modified alginates are alginate polymers thatcontain a mixture of monomers defined by Formula Ia, Formula Ib, FormulaIIa and Formula IIb. In some embodiments, the mixture of monomers in themodified alginate are in percent compositions (Formula Ia: Formula Ib:Formula IIa: Formula IIb) of 1-99:1-99:1-99:1-99 with the understandingthat the sum of the percent compositions is equal to 100%. Individualintegers between each these ranges are contemplated and disclosed.

In some embodiments, R is, independently in one or more sites ofchemical modification,

-A-B(—C)_(δ),   Formula XVI

wherein

A is hydrogen or an organic grouping containing any number of carbonatoms, 1-carbon atoms, 1-20 carbon atoms, or 1-14 carbon atoms, andoptionally including one or more heteroatoms such as oxygen, sulfur, ornitrogen grouping in linear, branched, or cyclic structural formats,representative organic groupings being U₁. U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄,U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₄+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃,U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferablyU₁+Q₁+Q₃;

B, and C are, independently, absent, hydrogen, or an organic groupingcontaining any number of carbon atoms, 1-30 carbon atoms, 1-20 carbonatoms, or 1-14 carbon atoms, and optionally including one or moreheteroatoms such as oxygen, sulfur, or nitrogen grouping in linear,branched, or cyclic structural formats, representative organic groupingsbeing U₁. U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄,U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄,U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃; and

δ is an integer from, as valency permits, 0 to 30.

In some embodiments, R₁ is, independently in one or more sites ofchemical modification,

—R₆—R^(b),   Formula XVIII

wherein

R₆ is hydrogen or an organic grouping containing any number of carbonatoms, 1-30 carbon atoms, 1-20 carbon atoms, or 1-14 carbon atoms, andoptionally including one or more heteroatoms such as oxygen, sulfur, ornitrogen grouping in linear, branched, or cyclic structural formats,representative R₆ organic groupings being U₁. U₁+Q₁; U₁+Q₂, U₁+Q₃,U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄,U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄,preferably U₁+Q₁+Q₃; and

R^(b) is absent, hydrogen, or an organic grouping containing any numberof carbon atoms, 1-30 carbon atoms, 1-20 carbon atoms, or 1-14 carbonatoms, and optionally including one or more heteroatoms such as oxygen,sulfur, or nitrogen grouping in linear, branched, or cyclic structuralformats, representative R^(b) organic groupings being U₁. U₁+Q₁, U₁+Q₂,U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of A and R₆, and independently incombination with any embodiments of any other relevant substituentclasses, A and R₆ can be, independently, hydrogen, U₁. U₁+Q₁, U₁+Q₂,U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of B, C, and R^(b), and independentlyin combination with any embodiments of any other relevant substituentclasses, B, C, and R^(b) can be, independently, absent, hydrogen, U₁.U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q_(x)+Q₃.

Independently in some embodiments of A and R₆, and independently incombination with any embodiments of any other relevant substituentclasses, A and R₆ can be, independently, hydrogen, amino, hydroxyl,thiol, oxo, phosphate, or J₁.

Independently in some embodiments of A and R₆, and independently incombination with any embodiments of any other relevant substituentclasses, A and R₆ can be, independently, hydrogen, amino, hydroxyl,thiol, oxo, phosphate, or J₂.

Independently in some embodiments of B, C, and R^(b), and independentlyin combination with any embodiments of any other relevant substituentclasses, B, C, and R^(b) can be, independently, absent, hydrogen, amino,hydroxyl, thiol, oxo, phosphate, or J₁.

Independently in some embodiments of B, C, and R^(b), and independentlyin combination with any embodiments of any other relevant substituentclasses, B, C, and R^(b) can be, independently, absent, hydrogen, amino,hydroxyl, thiol, oxo, phosphate, or J₂.

Independently in some embodiments of A and R₆, and independently incombination with any embodiments of any other relevant substituentclasses, A and R₆ can be, independently,

wherein y is an integer from 0-11; wherein w is an integer from 0-9;wherein k is an integer from 0 to 20;

wherein R^(d) and R^(e) are independently B, C, —B(—C)₆, R^(b), U₂,U₂+Q₁, U₂+Q₂, U₂+Q₃, U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃,U₂+Q₂+Q₄, U₂+Q₃+Q₄, U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄,and U₂+Q₁+Q₂+Q₃+Q₄, preferably U₂+Q₁+Q₃; or together with the carbonatom to which they are attached, form a 3- to 8-membered unsubstitutedor substituted carbocyclic or heterocyclic ring;

wherein X_(d) are independently absent, O, or S;

wherein R^(c) is B, C, —B(—C)_(δ), R^(b), absent, hydrogen, U₃. U₃+Q₁;U₃+Q₂, U₃+Q₃, U₃+Q₄, U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄,U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃, U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, andU₃+Q₁+Q₂+Q₃+Q₄, preferably U₃+Q₁+Q₃;

wherein R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are independently C, O, N, S,S(O), or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₃ are doubleor single according to valency, and wherein R₁₈ to R₂₃ are bound tonone, one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyB, C, absent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₄ is U₁.U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃; and

wherein R₁₀, R11, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independently B,C, hydrogen, U₁. U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃,U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄,U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

Independently in some embodiments of B, and independently in combinationwith any embodiments of any other relevant substituent classes, B can be

wherein y is an integer from 0-11; wherein w is an integer from 0-9;wherein k is an integer from 0 to 20;

wherein R^(d) and R^(e) are independently C, R^(b), U₂, U₂+Q₁, U₂+Q₂,U₂+Q₃, U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃, U₂+Q₂+Q₄,U₂+Q₃+Q₄, U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄, andU₂+Q₁+Q₂+Q₃+Q₄, preferably U₂+Q₁+Q₃; or together with the carbon atom towhich they are attached, form a 3- to 8-membered unsubstituted orsubstituted carbocyclic or heterocyclic ring;

wherein X_(d) are independently absent, O, or S;

wherein R^(c) is C, R^(b), absent, hydrogen, U₃. U₃+Q₁, U₃+Q₂, U₃+Q₃,U₃+Q₄, U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄,U₃+Q₁+Q₂+Q₃, U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄,preferably U₃+Q₁+Q₃;

wherein R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are independently C, O, N, S,S(O), or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₃ are doubleor single according to valency, and wherein R₁₈ to R₂₃ are bound tonone, one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)-, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyC, R^(b), absent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein IQ is 1%U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independently C,R^(b), hydrogen, U₁. U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃,U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄,U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃

Independently in some embodiments of R^(b), and independently incombination with any embodiments of any other relevant substituentclasses, R^(b) can be

wherein y is an integer from 0-11; wherein w is an integer from 0-9;wherein k is an integer from 0 to 20;

wherein R^(d) and R^(e) are independently C, U₂, U₂+Q₁, U₂+Q₂, U₂+Q₃,U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃, U₂+Q₂+Q₄, U₂+Q₃+Q₄, U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄, and U₂+Q₁+Q₂+Q₃+Q₄,preferably U₂+Q₁+Q₃; or together with the carbon atom to which they areattached, form a 3- to 8-membered unsubstituted or substitutedcarbocyclic or heterocyclic ring;

wherein X_(d) are independently absent, O, or S;

wherein R^(c) is C, absent, hydrogen, U₃, U₃+Q₁; U₃+Q₂, U₃+Q₃, U₃+Q₄,U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃,U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₄+Q₂+Q₃+Q₄, preferablyU₃+Q₄+Q₃;

wherein R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are independently C, O, N, S,S(O), or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₃ are doubleor single according to valency, and wherein R₁₈ to R₂₃ are bound tonone, one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyC, absent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₄ is 1% U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independently C,hydrogen, U₁; U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄,U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄,U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

Independently in some embodiments of C, and independently in combinationwith any embodiments of any other relevant substituent classes C can be

wherein y is an integer from 0-11; wherein w is an integer from 0-9;wherein k is an integer from 0 to 20;

wherein R^(d) and R^(e) are independently U₂, U₂+Q₁, U₂+Q₂, U₂+Q₃,U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃, U₂+Q₂+Q₄, U₂+Q₃+Q₄,U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄, and U₂+Q₁+Q₂+Q₃+Q₄,preferably U₂+Q₁+Q₃; or together with the carbon atom to which they areattached, form a 3- to 8-membered unsubstituted or substitutedcarbocyclic or heterocyclic ring;

wherein X_(d) are independently absent, O, or S;

wherein R^(c) is absent, hydrogen, U₃, U₃+Q₁, U₃+Q₂, U₃+Q₃, U₃+Q₄,U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃,U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄, preferablyU₃+Q₁+Q₃;

wherein R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are independently C, O, N, S,S(O), or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₃ are doubleor single according to valency, and wherein R₁₈ to R₂₃ are bound tonone, one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyabsent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₄ is U₁. U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independentlyhydrogen, U₁. U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄,U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄,U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

Independently in some embodiments of A and R₆, and independently incombination with any embodiments of any other relevant substituentclasses. A and R₆ can be, independently,

wherein y is an integer from 0-11; wherein w is an integer from 0-9;

wherein R^(d) and R^(e) are independently B, C, —B(—C)6, R^(b), U₂,U₂+Q₁, U₂+Q₂, U₂+Q₃, U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃,U₂+Q₂+Q₄, U₂+Q₃+Q₄, U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄,and U₂+Q₁+Q₂+Q₃+Q₄, preferably U₂+Q₁+Q₃; or together with the carbonatom to which they are attached, form a 3- to 8-membered unsubstitutedor substituted carbocyclic or heterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are independently C, O, N, S,S(O), or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₃ are doubleor single according to valency, and wherein R₁₈ to R₂₃ are bound tonone, one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyB, C, absent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₄ is U₁;U₁+Q₁; U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of B, and independently in combinationwith any embodiments of any other relevant substituent classes, B can be

wherein y is an integer from 0-11; wherein w is an integer from 0-9;

wherein R^(d) and R^(e) are independently C, R^(b), U₂, U₂+Q₁, U₂+Q₂,U₂+Q₃, U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃, U₂+Q₂+Q₄,U₂+Q₃+Q₄, U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄, andU₂+Q₁+Q₂+Q₃+Q₄, preferably U₂+Q₁+Q₃; or together with the carbon atom towhich they are attached, form a 3- to 8-membered unsubstituted orsubstituted carbocyclic or heterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are independently C, O, N, S,S(O), or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₃ are doubleor single according to valency, and wherein R₁₈ to R₂₃ are bound tonone, one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyC, R^(b), absent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₄ is U₁;U₁+Q₁; U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of R^(b), and independently incombination with any embodiments of any other relevant substituentclasses, R^(b) can be

wherein y is an integer from 0-11; wherein w is an integer from 0-9;

wherein R^(d) and R^(e) are independently C, U₂, U₂+Q₁, U₂+Q₂, U₂+Q₃,U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃, U₂+Q₂+Q₄, U₂+Q₃+Q₄,U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄, and U₂+Q₁+Q₂+Q₃+Q₄,preferably U₂+Q₁+Q₃; or together with the carbon atom to which they areattached, form a 3- to 8-membered unsubstituted or substitutedcarbocyclic or heterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are independently C, O, N, S,S(O), or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₃ are doubleor single according to valency, and wherein R₁₈ to R₂₃ are bound tonone, one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyC, absent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₄ is U₁; U₁+Q₁;U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of C, and independently in combinationwith any embodiments of any other relevant substituent classes, C can be

wherein y is an integer from 0-11; wherein w is an integer from 0-9;

wherein R^(d) and R^(e) are independently U₂, U₂+Q₁, U₂+Q₂, U₂+Q₃,U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃, U₂+Q₂+Q₄, U₂+Q₃+Q₄,U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄, and U₂+Q₁+Q₂+Q₃+Q₄,preferably U₂+Q₁+Q₃; or together with the carbon atom to which they areattached, form a 3- to 8-membered unsubstituted or substitutedcarbocyclic or heterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are independently C, O, N, S,S(O), or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₃ are doubleor single according to valency, and wherein R₁₈ to R₂₃ are bound tonone, one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyabsent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₄ is U₁. U₁+Q₁;U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of A and Rb, and independently incombination with any embodiments of any other relevant substituentclasses, A and R₆ can be, independently,

wherein y is an integer from 0-11;

wherein R^(e) are independently B, C, —B(—C)_(δ), R^(b), U₂, U₂+Q₁,U₂+Q₂, U₂+Q₃, U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃, U₂+Q₂+Q₄,U₂+Q₃+Q₄, U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄, andU₂+Q₁+Q₂+Q₃+Q₄, preferably U₂+Q₁+Q₃; or together with the carbon atom towhich they are attached, form a 3- to 8-membered unsubstituted orsubstituted carbocyclic or heterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are independently C, O, N, S,S(O), or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₃ are doubleor single according to valency, and wherein R₁₈ to R₂₃ are bound tonone, one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyB, C, absent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₄ is U₁;U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of B, and independently in combinationwith any embodiments of any other relevant substituent classes, B can be

wherein y is an integer from 0-11;

wherein R^(e) are independently C, R^(b), U₂, U₂+Q₁, U₂+Q₂, U₂+Q₃,U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃, U₂+Q₂+Q₄, U₂+Q₃+Q₄,U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄, and U₂+Q₁+Q₂+Q₃+Q₄.preferably U₂+Q₁+Q₃; or together with the carbon atom to which they areattached, form a 3- to 8-membered unsubstituted or substitutedcarbocyclic or heterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are independently C, O, N, S,S(O), or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₃ are doubleor single according to valency, and wherein R₁₈ to R₂₃ are bound tonone, one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyC, R^(b), absent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₄ is U₁;U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of R^(b), and independently incombination with any embodiments of any other relevant substituentclasses, R^(b) can be

wherein y is an integer from 0-11;

wherein R^(c) are independently C, U₂, U₂+Q₁, U₂+Q₂, U₂+Q₃, U₂+Q₄,U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃, U₂+Q₂+Q₄, U₂+Q₃+Q₄, U₂+Q₄+Q₂+Q₃,U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄, and U₂+Q₁+Q₂+Q₃+Q₄, preferablyU₂+Q₁+Q₃; or together with the carbon atom to which they are attached,form a 3- to 8-membered unsubstituted or substituted carbocyclic orheterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are independently C, O, N, S,S(O), or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₃ are doubleor single according to valency, and wherein R₁₈ to R₂₃ are bound tonone, one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyC, absent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₁ is 1% U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of C, and independently in combinationwith any embodiments of any other relevant substituent classes, C can be

wherein y is an integer from 0-11;

wherein R^(e) are independently U₂, U₂+Q₁, U₂+Q₂, U₂+Q₃, U₂+Q₄,U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃, U₂+Q₂+Q₄, U₂+Q₃+Q₄, U₂+Q₁+Q₂+Q₃,U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄, and U₂+Q₁+Q₂+Q₃+Q₄, preferablyU₂+Q₁+Q₃; or together with the carbon atom to which they are attached,form a 3- to 8-membered unsubstituted or substituted carbocyclic orheterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are independently C, O, N, S,S(O), or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₃ are doubleor single according to valency, and wherein R₁₈ to R₂₃ are bound tonone, one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyabsent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₄ is U₁, U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q_(x)+Q₃.

Independently in some embodiments of A and Rb, and independently incombination with any embodiments of any other relevant substituentclasses, A and R₆ can be, independently,

wherein w is an integer from 0-9;

wherein R^(d) and R^(e) are independently B, C, —B(—C)_(δ), R^(b), U₂,U₂+Q₁, U₂+Q₂, U₂+Q₃, U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃,U₂+Q₂+Q₄, U₂+Q₃+Q₄, U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄,and U₂+Q₁+Q₂+Q₃+Q₄, preferably U₂+Q₁+Q₃; or together with the carbonatom to which they are attached, form a 3- to 8-membered unsubstitutedor substituted carbocyclic or heterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are independently C, O, N, S, S(O),or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₂ are double orsingle according to valency, and wherein R₁₈ to R₂₂ are bound to none,one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyB, C, absent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₄ isU₁,U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₁+Q₃,U₁+Q₂+Q₄, U₄+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of B, and independently in combinationwith any embodiments of any other relevant substituent classes, B can be

wherein w is an integer from 0-9;

wherein R^(d) and R^(e) are independently C, R^(b), U₂, U₂+Q₁, U₂+Q₂,U₂+Q₃, U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃, U₂+Q₂+Q₄,U₂+Q₃+Q₄, U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄, andU₂+Q₁+Q₂+Q₃+Q₄, preferably U₂+Q₁+Q₃; or together with the carbon atom towhich they are attached, form a 3- to 8-membered unsubstituted orsubstituted carbocyclic or heterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are independently C, O, N, S, S(O),or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₂ are double orsingle according to valency, and wherein R₁₈ to R₂₂ are bound to none,one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)-, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyC, R^(b), absent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein IQ is U₁,U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₁+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of R^(b), and independently incombination with any embodiments of any other relevant substituentclasses, R^(b) can be

wherein w is an integer from 0-9;

wherein R^(d) and R^(e) are independently C, U₂, U₂+Q₁, U₂+Q₂, U₂+Q₃,U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃, U₂+Q₂+Q₄, U₂+Q₃+Q₄,U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄, and U₂+Q₁+Q₂+Q₃+Q₄.preferably U₂+Q₁+Q₃; or together with the carbon atom to which they areattached, form a 3- to 8-membered unsubstituted or substitutedcarbocyclic or heterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are independently C, O, N, S, S(O),or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₂ are double orsingle according to valency, and wherein R₁₈ to R₂₂ are bound to none,one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyC, absent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₄ is U₁, U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of C, and independently in combinationwith any embodiments of any other relevant substituent classes, C can be

wherein w is an integer from 0-9;

wherein R^(d) and R^(e) are independently U₂, U₂+Q₁, U₂+Q₂, U₂+Q₃,U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃, U₂+Q₂+Q₄, U₂+Q₃+Q₄,U₂+Q₁+Q₂+Q₃, U2+Q₁+Q₂+Q₄, U2+Q₁+Q₃+Q₄, U2+Q₂+Q₃+Q₄, and U2+Q₁+Q₂+Q₃+Q₄,preferably U₂+Q₁+Q₃; or together with the carbon atom to which they areattached, form a 3- to 8-membered unsubstituted or substitutedcarbocyclic or heterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are independently C, O, N, S, S(O),or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₂ are double orsingle according to valency, and wherein R₁₈ to R₂₂ are bound to none,one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyabsent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₄ is U₁, U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of A and Rb, and independently incombination with any embodiments of any other relevant substituentclasses, A and R₆ can be, independently,

wherein w is an integer from 0-9;

wherein R^(d) and R^(e) are independently B, C, —B(—C)_(δ), R^(b), U₂,U₂+Q₁, U₂+Q₂, U₂+Q₃, U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃,U₂+Q₂+Q₄, U₂+Q₃+Q₄, U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄,and U₂+Q₁+Q₂+Q₃+Q₄, preferably U₂+Q₁+Q₃; or together with the carbonatom to which they are attached, form a 3- to 8-membered unsubstitutedor substituted carbocyclic or heterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are independently C or N, whereinthe bonds between adjacent R₁₈ to R₂₂ are double or single according tovalency, wherein one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂are N and the others are C, and wherein R₁₈ to R₂₂ are bound to none,one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyB, C, absent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₄ is U₁,U₁+Q₁; U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of B, and independently in combinationwith any embodiments of any other relevant substituent classes, B can be

wherein w is an integer from 0-9;

wherein R^(d) and R^(e) are independently C, R^(b), U₂, U₂+Q₁, U₂+Q₂,U₂+Q₃, U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃, U₂+Q₂+Q₄,U₂+Q₃+Q₄, U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄, andU₂+Q₁+Q₂+Q₃+Q₄, preferably U₂+Q₁+Q₃; or together with the carbon atom towhich they are attached, form a 3- to 8-membered unsubstituted orsubstituted carbocyclic or heterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are independently C or N, whereinthe bonds between adjacent R₁₈ to R₂₂ are double or single according tovalency, wherein one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂are N and the others are C, and wherein R₁₈ to R₂₂ are bound to none,one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)-, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyC, R^(b), absent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₄ is U₁,U₁+Q₁; U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of R^(b), and independently incombination with any embodiments of any other relevant substituentclasses, R^(b) can be

wherein w is an integer from 0-9;

wherein R^(d) and R^(e) are independently C, U₂, U₂+Q₁, U₂+Q₂, U₂+Q₃,U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃, U₂+Q₂+Q₄, U₂+Q₃+Q₄,U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄, and U₂+Q₁+Q₂+Q₃+Q₄,preferably U₂+Q₁+Q₃; or together with the carbon atom to which they areattached, form a 3- to 8-membered unsubstituted or substitutedcarbocyclic or heterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are independently C or N, whereinthe bonds between adjacent R₁₈ to R₂₂ are double or single according tovalency, wherein one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂are N and the others are C, and wherein R₁₈ to R₂₂ are bound to none,one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyC, absent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₄ is U₁; U₁+Q₁;U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₄+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of C, and independently in combinationwith any embodiments of any other relevant substituent classes, C can be

wherein w is an integer from 0-9;

wherein R^(d) and R^(e) are independently U₂, U₂+Q₁, U₂+Q₂, U₂+Q₃,U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃, U₂+Q₂+Q₄, U₂+Q₃+Q₄,U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄, and U₂+Q₁+Q₂+Q₃+Q₄,preferably U₂+Q₁+Q₃; or together with the carbon atom to which they areattached, form a 3- to 8-membered unsubstituted or substitutedcarbocyclic or heterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are independently C or N, whereinthe bonds between adjacent R₁₈ to R₂₂ are double or single according tovalency, wherein one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂are N and the others are C, and wherein R₁₈ to R₂₂ are bound to none,one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)-, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyabsent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₄ is U₁; U₂+Q₁;U₂+Q₂, U₂+Q₃, U₂+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of A and R₆, and independently incombination with any embodiments of any other relevant substituentclasses, A and R₆ can be, independently,

wherein k is an integer from 0 to 20;

wherein X_(d) are independently absent, O, or S;

wherein R^(c) is B, C, —B(—C)_(δ), R^(b), absent, hydrogen, U₃, U₃+Q₁;U₃+Q₂, U₃+Q₃, U₃+Q₄, U₃+Q₁+Q₂, U₃+Q₁+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄,U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃, U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, andU₃+Q₁+Q₂+Q₃+Q₄, preferably U₃+Q₁+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independently B,C, R^(b), hydrogen, U₁, U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃,U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄,U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃

Independently in some embodiments of B, and independently in combinationwith any embodiments of any other relevant substituent classes, B can be

wherein k is an integer from 0 to 20;

wherein X_(d) are independently absent, O, or S;

wherein R^(c) is C, R^(b), absent, hydrogen, U₃, U₃+Q₁, U₃+Q₂, U₃+Q₃,U₃+Q₄, U₃+Q₁+Q₂, U₃+Q₁+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄,U₃+Q₁+Q₂+Q₃, U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄,preferably U₃+Q₁+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independently C,R^(b), hydrogen, U₁; U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃,U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄,U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃

Independently in some embodiments of R^(b), and independently incombination with any embodiments of any other relevant substituentclasses, R^(b) can be

wherein k is an integer from 0 to 20;

wherein X₄ are independently absent, O, or S;

wherein R^(c) is C, absent, hydrogen, U₃, U₃+Q₁, U₃+Q₂, U₃+Q₃, U₃+Q₄,U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃,U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄, preferablyU₃+Q₁+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independently C,hydrogen, U₁; U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄,U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄,U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

Independently in some embodiments of C, and independently in combinationwith any embodiments of any other relevant substituent classes, C can be

wherein k is an integer from 0 to 20;

wherein X_(d) are independently absent, O, or S;

wherein R^(c) is absent, hydrogen, U₃, U₃+Q₁; U₃+Q₂, U₃+Q₃, U₃+Q₄,U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃,U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄, preferablyU₃+Q₁+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independentlyhydrogen, U₁, U₁+Q₁; U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄,U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄,U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

Independently in some embodiments of A and R₆, and independently incombination with any embodiments of any other relevant substituentclasses, A and R₆ can be, independently,

wherein k is an integer from 0 to 20;

wherein X₄ are independently O or S;

wherein R^(c) is B, C, —B(—C)_(δ), R^(b), absent, hydrogen, U_(3j)U₃+Q₁,U₃+Q₂, U₃+Q₃, U₃+Q₄, U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄,U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃, U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, andU₃+Q₁+Q₂+Q₃+Q₄, preferably U₃+Q₁+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independently B,C, R^(b), hydrogen, U₁. U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃,U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄,U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃

Independently in some embodiments of B, and independently in combinationwith any embodiments of any other relevant substituent classes, B can be

wherein k is an integer from 0 to 20;

wherein X_(d) are independently O or S;

wherein R^(c) is C, R^(b), absent, hydrogen, U₃, U₃+Q₁; U₃+Q₂, U₃+Q₃,U₃+Q₄, U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄,U₃+Q₁+Q₂+Q₃, U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄,preferably U₃+Q₄+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independently C,R^(b), hydrogen, U₁. U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃,U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄,U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃

Independently in some embodiments of R^(b), and independently incombination with any embodiments of any other relevant substituentclasses, R^(b) can be

wherein k is an integer from 0 to 20;

wherein X₄ are independently O or S;

wherein R^(c) is C, absent, hydrogen, U₃, U₃+Q₁, U₃+Q₂, U₃+Q₃, U₃+Q₄,U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃,U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄, preferablyU₃+Q₁+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independently C,hydrogen, U₁. U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₄+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄,U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄,U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

Independently in some embodiments of C, and independently in combinationwith any embodiments of any other relevant substituent classes, C can be

wherein k is an integer from 0 to 20;

wherein X_(d) are independently O or S;

wherein R^(c) is absent, hydrogen, U₃, U₃+Q₁, U₃+Q₂, U₃+Q₃, U₃+Q₄,U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃,U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄, preferablyU₃+Q₁+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independentlyhydrogen, U₁. U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄,U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄,U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

Independently in some embodiments of A and R₆, and independently incombination with any embodiments of any other relevant substituentclasses, A and R₆ can be, independently,

wherein k is an integer from 1 to 20;

wherein X_(d) are O;

wherein R^(c) is B, C, —B(—C)_(δ), R^(b), U₃+U₃+Q₁; U₃+Q₂, U₃+Q₃, U₃+Q₄,U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃,U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₄+Q₂+Q₃+Q₄, preferablyU₃+Q₄+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independently B,C, R^(b), hydrogen, U₁. U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃,U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄,U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃

Independently in some embodiments of B, and independently in combinationwith any embodiments of any other relevant substituent classes, B can be

wherein k is an integer from 1 to 20;

wherein X₄ are O;

wherein R^(c) is C, R^(b), absent, hydrogen, U₃, U₃+Q₁, U₃+Q₂, U₃+Q₃,U₃+Q₄, U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄,U₃+Q₁+Q₂+Q₃, U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄,preferably U₃+Q₁+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independently C,R^(b), hydrogen, U₁. U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃,U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄,U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

Independently in some embodiments of R^(b), and independently incombination with any embodiments of any other relevant substituentclasses, R^(b) can be

wherein k is an integer from 1 to 20;

wherein X_(d) are O;

wherein R^(c) is C, absent, hydrogen, U₃, U₃+Q₁, U₃+Q₂, U₃+Q₃, U₃+Q₄,U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃,U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₄+Q₂+Q₃+Q₄, preferablyU₃+Q₄+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independently C,hydrogen, U₁, U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄,U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄,U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

Independently in some embodiments of C, and independently in combinationwith any embodiments of any other relevant substituent classes, C can be

wherein k is an integer from 1 to 20;

wherein X_(d) are O;

wherein R^(c) is absent, hydrogen, U₃, U₃+Q₁, U₃+Q₂, U₃+Q₃, U₃+Q₄,U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃,U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄, preferablyU₃+Q₁+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independentlyhydrogen, Up U₁+Q₁; U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄,U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄,U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

In some embodiments, modified alginates are alginate polymers thatcontain one or more covalently modified monomers defined by Formula I

wherein, in some embodiments, the modified alginate is defined byFormula Ia, Formula Ib, or a combination of Formula Ia and Formula Ib

wherein, independently for Formula I, Formula Ia, and Formula Ib,

X is oxygen, sulfur, or NR₄;

R₁ is, independently in the one or more modified monomers

wherein a is an integer from 1 to 30, z is an integer from 0 to 5, n isan integer from 1 to 12, m is an integer from 3 to 16, and R^(a) andR^(b) are independently selected from U₃, U₃+Q₁; U₃+Q₂, U₃+Q₃, U₃+Q₄,U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃,U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄, preferablyU₃+Q₁+Q₂+Q₃; or together with the carbon atom to which they areattached, form a 3- to 8-membered unsubstituted or substitutedcarbocyclic or heterocyclic ring;wherein

Y₁ and Y₂ independently are hydrogen or —PO(OR₅)₂; or

Y₂ is absent, and Y₁. together with the two oxygen atoms to which Y₁ andY₂ are attached form a cyclic structure as shown in Formula II, FormulaIIa, Formula IIb, or a combination of Formula IIa and Formula IIb,

wherein, independently for Formula II, Formula IIa, and Formula IIb,

R₂ and R₃ are, independently, hydrogen or an organic grouping containingany number of carbon atoms, 1-30 carbon atoms, 1-20 carbon atoms, or1-14 carbon atoms, and optionally including one or more heteroatoms suchas oxygen, sulfur, or nitrogen grouping in linear, branched, or cyclicstructural formats, representative R₂ and R₃ groupings being thosepresent in U₁, U₁+Q₁; U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄,U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄,U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃: or

R₂ and R₃, together with the carbon atom to which they are attached,form a 3- to 8-membered unsubstituted or substituted carbocyclic orheterocyclic ring; and

R₄, R₅, R₆, R₈, and R₁₀ are, independently, hydrogen or an organicgrouping containing any number of carbon atoms, 1-30 carbon atoms, 1-20carbon atoms, or 1-14 carbon atoms, and optionally including one or moreheteroatoms such as oxygen, sulfur, or nitrogen grouping in linear,branched, or cyclic structural formats, representative organic groupingsbeing those present in U₁; U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂,U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃,U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferablyU₁+Q₁+Q₃.

Modified alginate polymers can contain any ratio of mannuronatemonomers, guluronate monomers, and covalently modified monomers. Inpreferred embodiments, greater than 5%, greater than 10%, greater than15%, greater than 20%, more preferably greater than 25%, and mostpreferably greater than 30%, of the monomers in the modified alginatepolymer are covalently modified monomers.

In preferred embodiments, the modified alginate polymer can be ionicallycrosslinked to form hydrogels using a polyvalent ion, such as Ca²⁺,Sr²⁺, or Ba²⁺. The ability of modified alginates to form stablehydrogels in physiological conditions can be quantified using thehydrogel formation assay described herein. In preferred embodiments, themodified alginate polymer forms hydrogels such that the fluorescenceintensity measured using the high throughput assay described herein isbetween 15,000 and 55,000, preferably between 20,000 and 55,000, morepreferably between 25,000 and 55,000.

In preferred embodiments, the modified alginate is biocompatible, andinduces a lower foreign body response than unmodified alginate. Thebiocompatibility of modified alginates can be quantitatively determinedusing in vitro and in vivo assays known in the field, including the invivo biocompatibility assay described herein. In preferred embodiments,the modified alginate polymer is biocompatible such that thefluorescence response normalized to unmodified alginate measured usingthe in vivo biocompatibility assay described herein is less than 75%,70%, 65%, 60%, 55%, or 50%. Also described are assays for thecharacterization of modified alginate polymers.

A high throughput assay useful to characterize the ability of modifiedalginate polymers to form hydrogels is also described. In someembodiments, the hydrogel formation assay described herein is used toquantify the stability of hydrogels formed from alginates or modifiedalginates. In preferred embodiments, the hydrogel formation assaydescribed herein is used as a screening tool to identify modifiedalginates capable of forming stable hydrogels. The high throughput invivo biocompatibility assay described herein is used to identifymodified alginates which induce a lower foreign body response thanunmodified alginate. Assays are also provided for quantifying thebiocompatibility of modified alginates.

In some embodiments, the disclosed capsules and products can include acargo or payload, such as a biological material. For example, thebiological material can be cells or tissue. In some embodiments, thecargo is disposed within an outer member (e.g. a coating orencapsulating layer) that includes compounds as described herein on itssurface.

Further described herein are methods of coating medical products,devices, and surfaces using modified alginate polymers. In particularembodiments, the modified alginate polymers described herein are used tocoat products, devices, and surfaces for use in methods of treating adisease or disorder in a human or animal patient. In some embodiments, adisease or disorder in a human or animal patient is treated bytransplanting or implanting products, devices, and surfaces coated witha modified alginate polymer. In particular embodiments, a disease ordisorder in a human or animal patient is treated by transplanting orimplanting products, devices, and surfaces coated with a modifiedalginate polymer.

Further described herein are methods of encapsulating biologicalmaterials using modified alginate polymers. In particular embodiments,the modified alginate polymers described herein are used to encapsulatecells for use in methods of treating a disease or disorder in a human oranimal patient. In some embodiments, a disease or disorder in a human oranimal patient is treated by transplanting exogenous biological materialencapsulated in a modified alginate polymer. In particular embodiments,a disease or disorder in a human or animal patient is treated bytransplanting cells encapsulated in a modified alginate polymer. In amore particular embodiment, diabetes is treated by transplantingpancreatic islet cells encapsulated in a modified alginate polymer.

Cells suitable for encapsulation and transplantation are preferablysecretory or metabolic cells (i.e., they secrete a therapeutic factor ormetabolize toxins, or both) or structural cells (e.g., skin, muscle,blood vessel), or metabolic cells (e.g., they metabolize toxicsubstances). In some embodiments, the cells are naturally secretory,such as islet cells that naturally secrete insulin, or naturallymetabolic, such as hepatocytes that naturally detoxify and secrete. Insome embodiments, the cells are bioengineered to express a recombinantprotein, such as a secreted protein or metabolic enzyme. Depending onthe cell type, the cells may be organized as single cells, cellaggregates, spheroids, or even natural or bioengineered tissue.

In some embodiments, modified alginates are alginate polymers thatcontain one or more covalently modified monomers defined by Formula I

wherein, in some embodiments, the modified alginate is defined byFormula Ia, Formula Ib, or a combination of Formula Ia and Formula Ib

wherein, independently for Formula I, Formula Ia, and Formula Ib,

Y₁ and Y₂ independently are hydrogen;

X is oxygen, sulfur, or NR₄; wherein R₄ is hydrogen, alkyl, orsubstituted alkyl;

R₁ is, independently in one or more sites of chemical modification,

-A-B(—C)_(δ),   Formula XVI

wherein

A is

in A, R₂₄ is —(CR₂₅R₂₅)_(p); each R₂₅ is hydrogen; p is an integer from0 to 5; each R^(e) is independently alkyl, alkenyl, alkynyl, substitutedalkyl, substituted alkenyl, substituted alkynyl, alkoxy, alkylamino,dialkylamino, hydroxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, substituted alkoxy, carboxyl, substituted carboxyl, amino,substituted amino, amido, substituted amido, C₃-C₂₀ cyclic, substitutedC₃-C₂₀ cyclic, heterocyclic, or substituted heterocyclic; y is aninteger from 0-11; R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are independently Cor N, wherein the bonds between adjacent R₁₂ to R₁₇ are double or singleaccording to valency, and wherein R₁₈ to R₂₃ are bound to none, one, ortwo hydrogens according to valency; and R₂₁ is connected to B;

B is

in B, R₂₄ is —(CR₂₅R₂₅)_(p); each R₂₅ is hydrogen; p is an integer from0 to 5; each R^(d) is independently alkyl, alkenyl, alkynyl, substitutedalkyl, substituted alkenyl, substituted alkynyl, alkoxy, alkylamino,dialkylamino, hydroxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, substituted alkoxy, carboxyl, substituted carboxyl, amino,substituted amino, amido, substituted amido, C₃-C₂₀ cyclic, substitutedC₃-C₂₀ cyclic, heterocyclic, or substituted heterocyclic; w is aninteger from 0 to 4; R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are independently C orN, wherein the bonds between adjacent R₁₈ to R₂₂ are double or singleaccording to valency, and wherein R₁₈ to R₂₂ are bound to none, one, ortwo hydrogens according to valency; and R₂₀ is connected to C;

C is

in C, R₂₄ is —(CR₂₅R₂₅)_(p)— or —(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—; pand q are independently integers from 0 to 5; X_(b) is absent, —O—, —S—,—S(O)—, or —S(O)₂—, or NR₄; each R₂₅ is hydrogen; R₄ is alkyl orsubstituted alkyl; R^(e) are independently independently alkyl, alkenyl,alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl,alkoxy, alkylamino, dialkylamino, hydroxy, aryl, substituted aryl,heteroaryl, substituted heteroaryl, substituted alkoxy, carboxyl,substituted carboxyl, amino, substituted amino, amido, substitutedamido, C₃-C₂₀ cyclic, substituted C₃-C₂₀ cyclic, heterocyclic, orsubstituted heterocyclic; y is an integer from 0 to 11; each R₁₈, R₁₉,R₂₀, R₂₁, R₂₂, and R₂₃ are independently C, O, N, or S, wherein thebonds between adjacent R₁₈ to R₂₃ are double or single according tovalency, and wherein R₁₈ to R₂₃ are bound to none, one, or two hydrogensaccording to valency; and

δ is 1.

In some embodiments, modified alginates are alginate polymers thatcontain one or more covalently modified monomers defined by Formula I

wherein, in some embodiments, the modified alginate is defined byFormula Ia, Formula Ib, or a combination of Formula Ia and Formula Ib

wherein, independently for Formula I, Formula Ia, and Formula Ib;

Y₁ and Y₂ independently are hydrogen;

X is oxygen, sulfur, or NR₄; wherein R₄ is hydrogen, alkyl, orsubstituted alkyl;

R₁ is, independently in one or more sites of chemical modification,

-A-B(—C)_(δ),   Formula XVI

wherein

A is

in A, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independentlyhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl,substituted arylalkyl, alkoxy, substituted alkoxy, aroxy, substitutedaroxy, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl,amino, substituted amino, amido, substituted amido, C₃-C₂₀ cyclic,substituted C₃-C₂₀ cyclic, heterocyclic, substituted heterocyclic,poly(ethylene glycol), or poly(lactic-co-glycolic acid); k is an integerfrom 0 to 20; each X_(d) is independently absent, O, or S; and R^(c) isB;

B is

in B, R₂₄ is —(CR₂₅R₂₅)_(p); each R₂₅ is hydrogen; p is an integer from0 to 5; each R^(d) is independently alkyl, alkenyl, alkynyl, substitutedalkyl, substituted alkenyl, substituted alkynyl, alkoxy, alkylamino,dialkylamino, hydroxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, substituted alkoxy, carboxyl, substituted carboxyl, amino,substituted amino, amido, substituted amido, C₃-C₂₀ cyclic, substitutedC₃-C₂₀ cyclic, heterocyclic, or substituted heterocyclic; w is aninteger from 0 to 4; R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are independently C orN, wherein the bonds between adjacent R₁₈ to R₂₂ are double or singleaccording to valency, and wherein R₁₈ to R₂₂ are bound to none, one, ortwo hydrogens according to valency; and R₂₀ is connected to C;

C is

in C, R₂₄ is —(CR₂₅R₂₅)_(p)— or —(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—; pand q are independently integers from 0 to 5; X_(b) is absent, —O—, —S—,—S(O)—, or —S(O)₂—, or NR₄; each R₂₅ is hydrogen; R₄ is alkyl orsubstituted alkyl; R^(e) are independently independently alkyl, alkenyl,alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl,alkoxy, alkylamino, dialkylamino, hydroxy, aryl, substituted aryl,heteroaryl, substituted heteroaryl, substituted alkoxy, carboxyl,substituted carboxyl, amino, substituted amino, amido, substitutedamido, C₃-C₂₀ cyclic, substituted C₃-C₂₀ cyclic, heterocyclic, orsubstituted heterocyclic; y is an integer from 0 to 11; each R₁₈, R₁₉,R₂₀, R₂₁, R₂₂, and R₂₃ are independently C, O, N, or S, wherein thebonds between adjacent R₁₈ to R₂₃ are double or single according tovalency, and wherein R₁₈ to R₂₃ are bound to none, one, or two hydrogensaccording to valency; and

δ is 1.

In some embodiment, the capsules or product includes cells or tissuesencapsulated or coated with a modified polymer, where the polymerincludes compounds as described herein. In some embodiments:

(a) the polymer comprises modified alginate;

(b) the compound comprises the formula -A-B(—C)_(δ) (Formula XVI), whereA is Formula VII or Formula IX, B is Formula XIV, δ is 1, C is FormulaIX;

(c) the capsule or product is spherical or spheroidal in shape;

(d) the capsule or product has an average diameter of 1.5 mm;

(e) the cell is a cell producing a recombinant product; and, optionally,

(f) the capsule or product has a pore size of 0.1 to 1 pm.

In some embodiments, the capsule or product is provided as a preparationof capsules or products and the capsules or products in the preparationhave one or more of the following characteristics:

(1) at least 50% of the capsules or products in the preparation have asurface with a concentration of 1 to 5% surface modifications asmeasured by X-ray photoelectron spectroscopy (XPS);

(2) at least 50% of the capsules or products in the preparation have athe shape specified in (c);

(3) at least 50% of the capsules or products in the preparation have athe diameter specified in (d); and

(4) at least 50% of the capsules or products in the preparation have thepore size of(f).

In some embodiments, the capsule or product has properties (1) and (2).

In some embodiments, the capsule or product has properties (1) and (3).

In some embodiments, the capsule or product has properties (1) and (4).

In some embodiments, the capsule or product has properties (2) and (3).

In some embodiments, the capsule or product has properties (2) and (4).

In some embodiments, the capsule or product has properties (3) and (4).

In some embodiments, the capsule or product has properties (1), (2), and(3).

In some embodiments, the capsule or product has properties (1), (2),(3), and (4).

In some embodiments, when implanted into the subject, at least 5% of thecells are alive after 30 days.

In some embodiments, when implanted into the subject, the cells respondto an increase in blood glucose by secreting insulin.

In some embodiments, the polymer is singulary modified with the compoundof (b).

In some embodiments, the polymer is multiply modified with the compoundof (b) and another compound of different structure (for example, anothercompound as disclosed herein).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the general structure of the modified alginates obtainedusing the combinatorial synthetic approach described in Example 1. Thenumber of alginates prepared with each general structure is indicatedbelow.

FIG. 2 is a plot obtained from the hydrogel formation assay described inExample 2. The average fluorescence intensity values measured formodified alginates are plotted. Modified alginates yielding fluorescencevalues below 15,000 were considered unusable for applications wherehydrogel formation is critical (i.e. the encapsulation of cells).

FIG. 3 is a plot showing the effect of selected modified alginates onHeLa cell line viability as compared to the positive control (noalginate). Alginate (Alg) has a viability of 53%. Several polymers areshown to be more cytotoxic than Alg, however, the majority of thelibrary performs as well or better than Alg.

FIG. 4 is a plot obtained using the in vivo method described in Example5, which quantifies the biocompatibility of selected modified alginates.The fluorescence response obtained for the modified alginates using thein vivo method described in Example 5 was normalized to the fluorescenceresponse measured using unmodified alginate in order to quantify thebiocompatibility of the modified alginates in terms of % fluorescenceresponse.

FIG. 5 is a plot detailing the blood glucose level of mice transplantedwith rat islets encapsulated in selected modified alginates as well astwo different unmodified alginates (CMIT and CJOS). The dashed linerepresents normoglycemia in mice. At 5 days post-implantation, 287_F4,CJOS, 287_B4, 263_C12, and CMIT are above the dashed line while theothers are below the line. At 20 5 days post-implantation, the linesare, from top to bottom: CJOS, 287_G3, 287_F4, 287B_B4, CMIT, 287B_B8,263_C12, 263_C6, 287_B3, 287_D3, and 263_A7.

FIG. 6 is a bar graph showing inflammatory response (as measured byfluorescence normalized to VLVG) as a function of modified alginate(combined with unmodified alginate).

FIG. 7 is a diagram of the structures of amines, alcohols, azides, andalkynes used for the chemical modification of alginate. “N” designationindicates amidation reagents, “O” designations indicate esterificationreagents, and “Y” designations indicate click reagents.

FIG. 8 is a graph of FACS analysis of macrophages (CD11b+, CD68+) andneutrophils (CD11b+, Ly6g+) isolated from Z2-Y12, Z1-Y15, Z1-Y19, SLG20,and V/S capsules retrieved after 14 days in the IP space of C57BL/6mice. *** =p<0 0001, ns=not significant.

FIG. 9 is a diagram of the scheme for the synthesis of 774 alginateanalogues.

FIG. 10 is a graph of Western blot quantification of α-SMA proteinisolated from implants retrieved from the STZ-C57BL/6J.

FIG. 11 is a graph showing secondary cathepsin evaluation of 70 topmodified alginates from the initial screen formulated as 300 pmcapsules. Data normalized to the fluorescence of VLVG capsules. The tenalginate analogue capsules with the lowest cathepsin levels are on theright with lighter shading.

FIG. 12 is a graph of cytokine panel analysis (Elispot) of proteinextracted from 300 pm capsules of the top ten alginate analogue capsulesand control alginate capsules (SLG20, V/S) retrieved from the IP spaceof C57BL/6 mice after 14 days. For each cohort n=5. #indicate asignificance difference between the means with p<0.01.

FIG. 13 is a chemical structure of triazole-thiomorpholine dioxide(TMTD) alginate.

FIG. 14 is graphs of FACS analysis of encapsulated human cell implantsretrieved after 14 days IP in C57BL/6 showing macrophages andneutrophils.

FIG. 15 is graphs of FACS analysis of encapsulated human cell implantsretrieved after 14 days IP in C57BL/6 showing B cells and CD8 T cells.

DETAILED DESCRIPTION OF THE INVENTION

Alginates are a class of linear polysaccharide copolymers formed from1-4-glycosidically linked β-D-mannuronate (M) and its C-5 epimerα-L-guluronate (G). In some embodiments, alginates are formed fromα-D-mannuronate (M) and β-L-guluronate (G). The M and G residues arepresent in any ratio. Alginates are naturally occurring biopolymersproduced by a variety of organisms, including marine brown algae and atleast two genera of bacteria (Pseudomonas and Azotobacter). Typically,commercial alginates are isolated from marine algae, includingMacrocystis pyrifera, Ascophyllum nodosum, and various types ofLaminaria. Monomers of alginates are represented by the general formulaeshown below:

In some embodiments, the monomers of alginates are represented by

Three types of primary structure define the polysaccharide backbone ofalginates: homopolymeric regions of consecutive guluronate monomers(G-blocks), homopolymeric regions of consecutive mannuronate monomers(M-blocks), and regions containing alternating mannuronate andguluronate monomers (MG-blocks). The monomer blocks possess differentconformations in solution, ranging from a flexible extended structure(M-blocks) to a rigid compact structure (G-blocks). In the case ofG-blocks, the compact conformation facilitates the chelation ofmultivalent ions, notably Ca²⁺ ions, such that G-blocks in one alginatechain can be ionically crosslinked with G-blocks in another alginatechain, forming stable gels. As a result, the proportion, length, anddistribution of the monomer blocks influence the physiochemicalproperties of the alginate polymer.

In the case of commercially produced alginates obtained from algae, themolecular weight, primary structure, and overall molar ratio of uronicacid monomers (M/G ratio) in the alginate polymer depends on a number offactors, including the species producing the alginate, the time of yearin which the species is collected, and the location and age of the algalbody. As a result, alginates possessing a range of physiochemicalproperties, such as molecular weight and viscosity, are commerciallyavailable.

Alginates can be ionically crosslinked at room temperature and neutralpH to form hydrogels. The ability of alginates to form stable gels inphysiologically compatible conditions renders alginate gels useful in anumber of biomedical applications. For example, alginate gels have beused as a matrix for drug delivery to modulate the pharmacokinetics oftherapeutic, diagnostic, and prophylactic agents.

I. Definitions

“Alginate,” as used herein, is a collective term used to refer to linearpolysaccharides formed from β-D-mannuronate, α-L-guluronate,α-D-mannuronate, and β-L-guluronate in any M/G ratio, as well as saltsand derivatives thereof. M and G refer to the mannuronate and guluronateresidues in any of their anomeric configuration. M_(bD), G_(aL), M_(aD)and G_(bL) may be used to distinguish between β-D-mannuronate,α-L-guluronate, α-D-mannuronate, and β-L-guluronate, respectively. Theterm “alginate,” as used herein, encompasses any polymer having thestructure shown below, as well as salts thereof.

In some embodiments, the alginate is represented by the formula shownbelow, as well as salts thereof.

The modified alginate polymer exists in various charged states. In someembodiments, 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%,55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 90% and 99% of the monomers arecharged. In some embodiments, the charges arise from any unmodifiedcarboxylic acid groups, chemical modifications, or both, of the modifiedalginate polymer.

The salts of the alginates contain monovalent, divalent, polyvalentcations and combinations thereof, including, but not limited to Li⁺,Na⁺, K⁺, Rb⁺, Cs⁺, Mg²⁺, Ca²⁺, Sr²⁺, Ba²⁺, Al³⁺, Ga³⁺, Zn²⁺, Fe²⁺, Fe³⁺,Pb²⁺, Cu²⁺, Pb²⁺, Co²⁺ and Ni²⁺.

“Biocompatible,” as used herein, refers to a material which performs itsdesired function when introduced into an organism without inducingsignificant inflammatory response, immunogenicity, or cytotoxicity tonative cells, tissues, or organs. Biocompatibility, as used herein, canbe quantified using the in vivo biocompatibility assay described hereinin Example 5.

In this assay, a material or product as disclosed can be consideredbiocompatible if it produces, in a test of biocomptibilty related toimmune system reaction less than 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%,10%, 8%, 6%, 5%, 4%, 3%, 2%, or 1% of the reaction, in the same test ofbiocompatibility, produced by a material or product the same as the testmaterial or product except for a lack of the surface modification on thetest material or product. Examples of useful biocompatibility testsinclude measuring and assessing cytotoxicity in cell culture,inflammatory response after implantation (such as by fluorescencedetection of cathepsin activity), and immune system cells recruited toimplant (for example, macrophages and neutrophils).

“Foreign Body Response,” as used herein, refers to the immunologicalresponse of biological tissue to the presence of any foreign material inthe tissue which can include protein adsorption, macrophages,multinucleated foreign body giant cells, fibroblasts, and angiogenesis.

“Chemically Modified Alginate” or “Modified Alginate,” are used hereininterchangeably, and refer to alginate polymers which contain one ormore covalently modified monomers.

“Covalently Modified Monomer,” as used herein, refers to a monomer whichis an analog or derivative of a mannuronate and/or guluronate monomerobtained from a mannuronate and/or guluronate monomer via a chemicalprocess.

“Contacting” as used herein in the context of coating refers to any wayfor coating a polymer, such as the modified alginate polymers disclosedherein, on a substrate or surface. Contacting can include, but is notlimited to, intraoperative dip-coating, spraying, wetting, immersing,dipping, painting, bonding or adhering, stepwise surface derivatization,or otherwise providing a substrate or surface with a compound with thehydrophobic, poly cationic polymer. The polymer can be covalently ornon-covalently attached to the substrate or surface. In someembodiments, the polymer is non-covalently associated with the surface.

“Coating” as used herein refers to any temporary, semipermanent orpermanent layer, covering or surface. A coating can be applied as a gas,vapor, liquid, paste, semi-solid, or solid. In addition a coating can beapplied as a liquid and solidified into a hard coating. Elasticity canbe engineered into coatings to accommodate pliability, e.g. swelling orshrinkage, of the substrate or surface to be coated. Preferred coatingsare modified alginate polymers disclosed herein.

“Surface” or “surfaces,” as used herein, refers to any surface of anysolid or semi-solid material, including glass, plastics, metals,polymers, and like. This includes surfaces constructed out of more thanone material, including coated surfaces.

“Corresponding material” and “similar material,” as used herein, refersa material that has, as far as is practical or possible, the samecomposition, structure, and construction as a reference material. Theterms “corresponding” and “similar” can be used for the same meaningwith any particular or subgroup of materials described herein. Forexample, a “similar surface modification” refers a surface modificationthat has, as far as is practical or possible, the same composition,structure, and construction as a reference surface modification.

“Control corresponding material” and “control similar material,” as usedherein, refers a material that has, as far as is practical or possible,the same composition, structure, and construction as a referencematerial except for one or more specified parameters. For example, acontrol corresponding material that lacks the chemical modification inreference to a chemically modified material refers to a material thathas, as far as is practical or possible, the same composition,structure, and construction as a reference material except for thechemical modification. Generally, a material prior to chemicalmodification constitutes a control corresponding material to thechemically modified form of the material. The terms “controlcorresponding” and “control similar” can be used for the same meaningwith any particular or subgroup of materials described herein. Forexample, a “control similar surface modification” refers a surfacemodification that has, as far as is practical or possible, the samecomposition, structure, and construction as a reference surfacemodification except for one or more specified parameters. Componentsthat are “control corresponding” or “control similar” relative to areference component are useful as controls in assays assessing theeffect of independent variables.

“Preparation,” as used herein in reference to capsules, compounds, andother objects and components themselves (as opposed to their productionor preparation), refers to a plurality of the capsule, compound, orother object or component, each such capsule, compound, or other objector component having a set of common properties and structure but alsohaving some differences in properties or structure. For example, apreparation of capsules with capsules having the same composition,structure, and functional properties, can include, for example, capsuleshaving a variance in shape, size, pore size, generally around a desiredmean. It is not necessary that such variance be intended or purposelydesigned, although that is contemplated. Rather, such variance generallyis a consequence of the variability in production or preparation of thecapsules, compounds, and other objects and components (as is exemplifiedby production of capsules).

“Implanting,” as used herein, refers to the insertion or grafting intothe body of a subject a product or material.

“Administering,” as used herein, refers to contacting a substance,material, or product to the body of a subject. For example,administering a substance, material, or a product includes contactingthe skin of a subject and injecting or implanting a substance, material,or product into the subject.

“Chemical compound,” as used herein, refers to an organic compound. Thedisclosed compounds for chemically modifying alginates are examples ofchemical compounds.

“High,” “higher,” “increases,” “elevates,” and “elevation,” as usedherein, refer to increases above a reference level, e.g., a basal level,e.g., as compared to a control. “Low,” “lower,” “reduces,” and“reduction,” as used herein, refer to decreases below a reference level,e.g., a basal level, e.g., as compared to a control. “Improved,” as usedherein, refers to a change that is desirable, which may be a higher orlower value of some measure.

“Long-term,” as used herein, refers to a state or situation that extendsfor longer than days or weeks. Preferred long-term effects last severalmonths or years.

“Monitoring” as used herein refers to any method in the art by which anactivity can be measured.

“Providing,” as used herein, refers to any method, device, or means ofadding a compound or molecule to something, e.g., a method or deviceknown in the art. Examples of providing can include the use of pipettes,pipettemen, syringes, needles, tubing, guns, etc. This can be manual orautomated. It can include transfection by any mean or any other means ofproviding nucleic acids to dishes, cells, tissue, cell-free systems andcan be in vitro or in vivo.

“Preventing,” as used herein, refers to administering or applying atreatment or therapy prior to the onset of clinical symptoms of adisease or conditions so as to prevent a physical manifestation ofaberrations associated with the disease or condition.

“In need of treatment,” as used herein, refers to a subject that wouldbenefit from the treatment. In some embodiments, it comprises a judgmentmade by a caregiver (e.g. physician, nurse, nurse practitioner, orindividual in the case of humans; veterinarian in the case of animals,including non-human mammals) that a subject requires or will benefitfrom treatment. This judgment can be made based on a variety of factorsthat are in the realm of a care giver's expertise, but that includes theknowledge that the subject is ill, or will be ill, as the result of acondition that is treatable by the compounds of the invention.

“Subject,” as used herein, includes, but is not limited to, animals,plants, bacteria, viruses, parasites and any other organism or entity.The subject can be a vertebrate, more specifically a mammal (e.g., ahuman, horse, pig, rabbit, dog, sheep, goat, non-human primate, cow,cat, guinea pig or rodent), a fish, a bird or a reptile or an amphibian.The subject can be an invertebrate, more specifically an arthropod(e.g., insects and crustaceans). The term does not denote a particularage or sex. Thus, adult and newborn subjects, as well as fetuses,whether male or female, are intended to be covered. A patient refers toa subject afflicted with a disease or disorder. The term “patient”includes human and veterinary subjects.

“Treatment” and “treating,” as used herein, refer to the medicalmanagement of a subject with the intent to cure, ameliorate, stabilize,or prevent a disease, pathological condition, or disorder. This termincludes active treatment, that is, treatment directed specificallytoward the improvement of a disease, pathological condition, ordisorder, and also includes causal treatment, that is, treatmentdirected toward removal of the cause of the associated disease,pathological condition, or disorder. In addition, this term includespalliative treatment, that is, treatment designed for the relief ofsymptoms rather than the curing of the disease, pathological condition,or disorder; preventative treatment, that is, treatment directed tominimizing or partially or completely inhibiting the development of theassociated disease, pathological condition, or disorder; and supportivetreatment, that is, treatment employed to supplement another specifictherapy directed toward the improvement of the associated disease,pathological condition, or disorder. It is understood that treatment,while intended to cure, ameliorate, stabilize, or prevent a disease,pathological condition, or disorder, need not actually result in thecure, ameliorization, stabilization or prevention. The effects oftreatment can be measured or assessed as described herein and as knownin the art as is suitable for the disease, pathological condition, ordisorder involved. Such measurements and assessments can be made inqualitative and/or quantitiative terms. Thus, for example,characteristics or features of a disease, pathological condition, ordisorder and/or symptoms of a disease, pathological condition, ordisorder can be reduced to any effect or to any amount.

A cell can be in vitro. Alternatively, a cell can be in vivo and can befound in a subject. A “cell” can be a cell from any organism including,but not limited to, a bacterium.

“Beneficial effect,” as used herein, refers to any effect that isdesired. In the context of the disclosed chemically modified alginates,beneficial effects include lower foreign body response, improvedbiocompatibility, and reduced immune response or reaction.

“Independently,” as used herein in the context of chemical formulae (andunless the context clearly indicates otherwise), means that eachinstance of the group referred to is chosen independently of the otherinstances of that group. For example, each instance of the group couldbe different from every other instance, some other instances, or noother instances of the group. Where multiple groups are referred to,“independently” means that each instance of each given group is chosenindependently of the other instances of the respective group and thateach of the groups are chosen independently of the other groups. Forexample, each instance of a first group could be different from everyinstance, some other instances, or no other instances of a second group(or third, or fourth, etc., group).

“Component” as used herein in the context of a product, e.g., medicalproducts, such as medical devices, is a part of a product that isstructurally integrated with that product. A component may be applied toa substrate or to the surface of a product, contained within thesubstance of the product, retained in the interior of the product, orany other arrangement whereby that part is an integral element of thestructure of the product. As an example, the silicone coveringsurrounding the mechanical part of a pacemaker is a component of thepacemaker. A component may be the lumen of a product where the lumenperforms some function essential to the overall function of the product.The lumen of a tissue expander port is a component of the tissueexpander. A component can refer to a reservoir or a discrete area withinthe product specifically adapted for the delivery of a fluid to asurface of the product. A reservoir within an implantable drug deliverydevice is a component of that device.

The phrase “effective amount,” as used herein in the context of acoating, generally refers to the amount of the coating applied to theimplant in order to provide one or more clinically measurable endpoints,such as reduced foreign body response compared to an uncoated implant,an implant coated with an unmodified coating, or another suitablecontrol. The phrase “effective amount,” as used herein in the context ofa cell, capsule, product, device, material, composition, or compound,refers to a nontoxic but sufficient amount of the cell, capsule,product, device, material, composition, or compound to provide thedesired result. The exact amount required may vary from subject tosubject, depending on the species, age, and general condition of thesubject; the severity of the disease that is being treated; theparticular cell, capsule, product, device, material, composition, orcompound used; its mode of administration; and other routine variables.An appropriate effective amount can be determined by one of ordinaryskill in the art using only routine experimentation.

“Singularly Modified Alginate Polymer,” as used herein, refers tomodified alginates that contain one or more covalently modifiedmonomers, wherein substantially all of the covalently modified monomerspossess the same covalent modification (i.e. the polymer contains one‘type’ or species of covalently modified monomer). Singularly modifiedalginate polymers include, for example, modified alginate polymerswherein substantially all of the monomers in the modified alginatepolymer are represented by mannuronate monomers, guluronate monomers,and a covalently modified monomer defined by Formula I. Not all of themonomers are necessarily covalently modified.

“Capsule,” as used herein, refers to a particle having a mean diameterof about 150 μm to about 5 cm, formed of a cross-linked hydrogel, havinga cross-linked hydrogel core that is surrounded by one or more polymericshells, having one or more cross-linked hydrogel layers, having across-linked hydrogel coating, or a combination thereof. The capsule mayhave any shape suitable for, for example, cell encapsulation. Thecapsule may contain one or more cells dispersed in the cross-linkedhydrogel, thereby “encapsulating” the cells. Reference to “capsules”herein refers to and includes microcapsules unless the context clearlyindicates otherwise. Preferred capsules have a mean diameter of about150 μm to about 8 mm.

“Microcapsule” and “microgel,” as used herein, are used interchangeablyto refer to a particle or capsule having a mean diameter of about 150 μmto about 1000 μm.

“Biological material,” as used herein, refers to any biologicalsubstance, including, but not limited to, tissue, cells, biologicalmicromolecules, such as a nucleotides, amino acids, cofactors, andhormones, biological macromolecules, such as nucleic acids,polypeptides, proteins (for example enzymes, receptors, secretoryproteins, structural and signaling proteins, hormones, ligands, etc.),polysaccharides, and/or any combination thereof.

“Cell,” as used herein, refers to individual cells, cell lines, primarycultures, or cultures derived from such cells unless specificallyindicated. “Culture,” as used herein, refers to a composition includingcells, such as isolated cells, which can be of the same or a differenttype. “Cell line,” as used herein, refers to a permanently establishedcell culture that will proliferate indefinitely given appropriate freshmedium and space, thus making the cell line “immortal.” “Cell strain,”as used herein, refers to a cell culture having a plurality of cellsadapted to culture, but with finite division potential. “Cell culture,”as used herein, is a population of cells grown on a medium such as agar.

Cells can be, for example, xenogeneic, autologous, or allogeneic. Cellscan also be primary cells. Cells can also be cells derived from theculture and expansion of a cell obtained from a subject. For example,cells can also be stem cells or derived from stem cells. Cells can alsobe immortalized cells. Cells can also be genetically engineered toexpress or produce a protein, nucleic acid, or other product.

“Mammalian cell,” as used herein, refers to any cell derived from amammalian subject.

“Autologous,” as used herein, refers to a transplanted biologicalmaterial, such as cells, taken from the same individual.

“Allogeneic,” as used herein, refers to a transplanted biologicalmaterial, such as cells, taken from a different individual of the samespecies.

“Xenogeneic,” as used herein, refers to a transplanted biologicalmaterial, such as cells, taken from a different species.

“Endocrine cell,” as used herein, refers to a cell of the endocrinesystem. “Secreting endocrine cell,” as used herein, refers to anendocrine cell that secretes one or more hormones.

“Islet cell,” as used herein, refers to an endocrine cell derived from amammalian pancreas. Islet cells include alpha cells that secreteglucagon, beta cells that secrete insulin and amylin, delta cells thatsecrete somatostatin, PP cells that secrete pancreatic polypeptide, orepsilon cells that secrete ghrelin. The term includes homogenous andheterogeneous populations of these cells. In preferred embodiments, apopulation of islet cells contains at least beta cells. In anembodiment, an islet cell is a human islet cell.

“Hormone-producing cell,” as used herein, refers to a cell that producesone or more hormones. Preferred hormone-producing cells produce hormonein response to physiological stimulus, such as the physiologicalstimulus that cause secretion of the hormone from an endocrine cell thatnaturally secretes the hormone. Secreting endocrine cells,hormone-producing cells derived from stem cells, and cells geneticallyengineered to produce hormone are examples of hormone-producing cells.

“Insulin-producing cell,” as used herein, refers to a cell that producesinsulin. Preferred insulin-producing cells produce insulin in responseto glucose levels. Islet beta cells, insulin-producing cells derivedfrom stem cells, and cells genetically engineered to produce insulin areexamples of insulin-producing cells.

“Transplant,” as used herein, refers to the transfer of a cell, tissue,or organ to a subject from another source. The term is not limited to aparticular mode of transfer. Encapsulated cells may be transplanted byany suitable method, such as by injection or surgical implantation.

“Primary cells,” “primary cell lines,” and “primary cultures,” as usedherein, are used interchangeably to refer to cells and cells culturesthat have been derived from a subject and allowed to grow in vitro for alimited number of passages, that is, splittings, of the culture.

“Mesenchymal stem cell” or “MSC,” as used herein, refer to multipotentstem cells present in or derived from mesenchymal tissue that candifferentiate into a variety of cell types, including: osteoblasts,chondrocytes, and adipocytes.

“Derived from,” as used herein, with respect to cells, refer to cellsobtained from tissue, cell lines, or cells, which optionally are thencultured, passaged, differentiated, induced, etc., to produce thederived cells. For example, induced pluripotent stem cells are derivedfrom somatic cells.

“Pluripotency,” as used herein, refers to the ability of cells todifferentiate into multiple types of cells in an organism. By“pluripotent stem cells,” it is meant cells that can self-renew anddifferentiate to produce all types of cells in an organism. By“multipotency” it is meant the ability of cells to differentiate intosome types of cells in an organism but not all, typically into cells ofa particular tissue or cell lineage.

“Multi-potent cells” and “adult stem cells,” as used herein, refer toany type of stem cell that is not derived from an embryo or fetus andgenerally has a limited capacity to generate new cell types (referred toas “multipotency”) and being committed to a particular lineage.

“Induced pluripotent stem cell,” as used herein, encompasses pluripotentstem cells, that, like embryonic stem (ES) cells, can be cultured over along period of time while maintaining the ability to differentiate intoall types of cells in an organism, but that, unlike ES cells (which arederived from the inner cell mass of blastocysts), are derived fromsomatic cells.

For clarity of discussion herein, singularly modified alginates aredefined using formulae illustrating the structure of the covalentlymodified monomers incorporated in the backbone and omitting themannuronate and guluronate monomers. For example, a singularly modifiedalginate polymer composed of mannuronate monomers, guluronate monomers,and a covalently modified monomer defined by Formula I, wherein X isNR₄, R₁ is methyl, and R₄, Y₁, and Y₂ are hydrogen, is illustratedherein by the structure below.

In some embodiments, the covalently modified monomer is derived fromFormula Ia or Formula Ib, shown below.

“Multiply Modified Alginate Polymer,” as used herein, refers to modifiedalginates that contain covalently modified monomers, whereinsubstantially all of the covalently modified monomers do not possess thesame covalent modification (i.e. the polymer contains two or moredifferent ‘types’ or species of covalently modified monomers). Multiplymodified alginate polymers include, for example, modified alginatepolymers wherein substantially all of the monomers in the modifiedalginate polymer are represented by mannuronate monomers, guluronatemonomers, and two or more different types of covalently modifiedmonomers defined by Formula I. As used in this context, a ‘type’ or‘species’ of covalently modified monomer refers to a covalent monomerdefined by Formula I, wherein all possible variable positions arechemically defined. Not all the monomers are covalently modified.

For clarity of discussion herein, modified alginates are defined usingformulae illustrating the covalently modified monomers incorporated inthe backbone and omitting the mannuronate and guluronate monomers. Forexample, a multiply modified alginate polymer composed of mannuronatemonomers, guluronate monomers, and two different types of covalentlymodified monomers, wherein the first type of covalently modified monomeris defined by Formula I, Formula Ia, Formula Ib, or a combination ofFormula Ia and Formula Ib, as described above, wherein X is NR₄, R₁ ismethyl, and R₄, Y₁; and Y₂ are hydrogen and the second type ofcovalently modified monomer is defined by Formula I, Formula Ia, orFormula Ib, wherein X is oxygen, R₁ is ethyl, and Y₁ and Y₂ arehydrogen, is illustrated by the structures below.

“Analog” and “Derivative,” in the context of chemical compounds, areused herein interchangeably, and refer to a compound having a structuresimilar to that of a parent compound, but varying from the parentcompound by a difference in one or more certain components. Analogs orderivatives differ from the parent compound in one or more atoms,functional groups, or substructures, which are replaced with otheratoms, groups, or substructures. An analog or derivative can be imaginedto be formed, at least theoretically, from the parent compound via somechemical or physical process. The terms analog and derivative encompasscompounds which retain the same basic ring structure as the parentcompound, but possess one or more different substituents on the ring(s).For example, analog or derivative of mannuronate or guluronate refers tocompounds which retain the core of the monomer, e.g., the pyranose ring,but differ in or more substitutents on the ring. In some embodiments, ananalog or derivative retains at least, 20, 30, 40, 50, 60, 70, 80, 90,or 100% of a selected activity of a reference compound, e.g., a parentcompound.

“Mannuronate” and “Mannuronate Monomer,” as used herein, refer tomannuronic acid monomers as well as salts thereof.

In some embodiments, the mannuronate is the structure shown below.

“Guluronate” and “Guluronate Monomer,” as used herein, refer toguluronic acid monomers as well as salts thereof.

In some embodiments, the guluronate is the structure shown below.

“Substantially,” as used herein, specifies an amount of 95% or more, 96%or more, 97% or more, 98% or more, or 99% or more.

“Glass Transition Temperature” (T_(g)), as used herein, refers to thetemperature at which a reversible transition is observed in amorphousmaterials from a hard and relatively brittle state into a molten orrubber-like state. T_(g) values for alginate polymers can beexperimentally determined using differential scanning calorimetry (DSC,heated and cooled at a rate of 10 K/min). In all cases herein, values ofT_(g) are measured using powder polymer samples.

“Click Chemistry,” as used herein, refers to chemical reactions used tocouple two compounds together which are high yielding, wide in scope,create only byproducts that can be removed without chromatography, arestereospecific, simple to perform, and can be conducted in easilyremovable or benign solvents. Examples of reactions which fulfill thesecriteria include the nucleophilic ring opening of epoxides andaziridines, non-aldol type carbonyl reactions, including the formationof hydrazones and heterocycles, additions to carbon-carbon multiplebonds, including Michael Additions, and cycloaddition reactions, such asa 1,3-dipolar cycloaddition reaction (i.e. a Huisgen cycloadditionreaction). See, for example, Moses, and Moorhouse, Chem Soc. Rev.36:1249-1262 (2007); Kolb and Sharpless, Drug Discovery Today. 8(24):1128-1137 (2003); and Kolb et al., Angew. Chem. Int. Ed. 40:2004-2021(2001).

“Polyvalent Cation,” as used herein, refers to cations which have apositive charge greater than 1. Examples include, but are not limitedto, Ca²⁺, Ba²⁺, and Sr²⁺.

“Substituted,” as used herein, refers to all permissible substituents ofthe compounds or functional groups described herein. In the broadestsense, the permissible substituents include acyclic and cyclic, branchedand unbranched, carbocyclic and heterocyclic, aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,but are not limited to, halogens, hydroxyl groups, or any other organicgroupings containing any number of carbon atoms, preferably 1-14 carbonatoms, and optionally include one or more heteroatoms such as oxygen,sulfur, or nitrogen grouping in linear, branched, or cyclic structuralformats. Representative substituents include alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl,substituted phenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, halo, hydroxyl, alkoxy, substituted alkoxy, phenoxy,substituted phenoxy, aroxy, substituted aroxy, alkylthio, substitutedalkylthio, phenylthio, substituted phenylthio, arylthio, substitutedarylthio, cyano, isocyano, substituted isocyano, carbonyl, substitutedcarbonyl, carboxyl, substituted carboxyl, amino, substituted amino,amido, substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid,phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl,polyaryl, substituted polyaryl, C₃-C₂₀ cyclic, substituted C₃-C₂₀cyclic, heterocyclic, substituted heterocyclic, amino acid,poly(lactic-co-glycolic acid), peptide, and polypeptide groups. Suchalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, halo, hydroxyl, alkoxy, substitutedalkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy,alkylthio, substituted alkylthio, phenylthio, substituted phenylthio,arylthio, substituted arylthio, cyano, isocyano, substituted isocyano,carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino,substituted amino, amido, substituted amido, sulfonyl, substitutedsulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl,substituted phosphonyl, polyaryl, substituted polyaryl, C₃-C₂₀ cyclic,substituted C₃-C₂₀ cyclic, heterocyclic, substituted heterocyclic, aminoacid, poly(lactic-co-glycolic acid), poly(lactic-co-glycolic acid),peptide, and polypeptide groups can be further substituted.

Heteroatoms such as nitrogen may have hydrogen substituents and/or anypermissible substituents of organic compounds described herein whichsatisfy the valences of the heteroatoms. It is understood that“substitution” or “substituted” includes the implicit proviso that suchsubstitution is in accordance with permitted valence of the substitutedatom and the substituent, and that the substitution results in a stablecompound, i.e. a compound that does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, etc.

Except where specifically and expressly provided to the contrary, theterm “substituted” refers to a structure, e.g., a chemical compound or amoiety on a larger chemical compound, regardless of how the structurewas formed. The structure is not limited to a structure made by anyspecific method.

“Aryl,” as used herein, refers to C₅-C₂₆-membered aromatic, fusedaromatic, fused heterocyclic, or biaromatic ring systems. Broadlydefined, “aryl,” as used herein, includes 5-, 6-, 7-, 8-, 9-, 10-, 14-,18-, and 24-membered single-ring aromatic groups that may include fromzero to four heteroatoms, for example, benzene, naphthalene, anthracene,phenanthrene, chrysene, pyrene, corannulene, coronene, etc.

“Aryl” further encompasses polycyclic ring systems having two or morecyclic rings in which two or more carbons are common to two adjoiningrings (i.e., “fused rings”) wherein at least one of the rings isaromatic, e.g., the other cyclic ring or rings can be cycloalkyls,cycloalkenyls, cycloalkynyls, aryls and/or heterocycles.

The term “substituted aryl” refers to an aryl group, wherein one or morehydrogen atoms on one or more aromatic rings are substituted with one ormore substituents including, but not limited to, halogen, azide, alkyl,aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, carbonyl (suchas a ketone, aldehyde, carboxyl, alkoxycarbonyl, formyl, or an acyl),silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate,or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate,phosphinate, amino (or quarternized amino), amido, amidine, imine,cyano, nitro, azido, sulfhydryl, imino, alkylthio, sulfate, sulfonate,sulfamoyl, sulfoxide, sulfonamido, sulfonyl, heterocyclyl, alkylaryl,haloalkyl (such as CF₃, —CH₂—CF₃, —CCl₃), —CN, aryl, heteroaryl, andcombinations thereof.

“Heterocycle,” “heterocyclic” and “heterocyclyl” are usedinterchangeably, and refer to a cyclic radical attached via a ringcarbon or nitrogen atom of a monocyclic or bicyclic ring containing 3-10ring atoms, and preferably from 5-6 ring atoms, consisting of carbon andone to four heteroatoms each selected from the group consisting ofnon-peroxide oxygen, sulfur, and N(Y) wherein Y is absent or is H, O,C₁-C₁₀ alkyl, phenyl or benzyl, and optionally containing 1-3 doublebonds and optionally substituted with one or more substituents.Heterocyclyl are distinguished from heteroaryl by definition. Examplesof heterocycles include, but are not limited to piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl,dihydrofuro[2,3-b]tetrahydrofuran, morpholinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pyranyl,2H-pyrrolyl, 4H-quinolizinyl, quinuclidinyl, tetrahydrofuranyl,6H-1,2,5-thiadiazinyl. Heterocyclic groups can optionally be substitutedwith one or more substituents as defined above for alkyl and aryl.

The term “heteroaryl” refers to C₅-C₂₆-membered aromatic, fusedaromatic, biaromatic ring systems, or combinations thereof, in which oneor more carbon atoms on one or more aromatic ring structures have beensubstituted with an heteroatom. Suitable heteroatoms include, but arenot limited to, oxygen, sulfur, and nitrogen. Broadly defined,“heteroaryl,” as used herein, includes 5-, 6-, 7-, 8-, 9-, 10-, 14-,18-, and 24-membered single-ring aromatic groups that may include fromone to four heteroatoms, for example, pyrrole, furan, thiophene,imidazole, oxazole, thiazole, triazole, tetrazole, pyrazole, pyridine,pyrazine, pyridazine and pyrimidine, and the like. The heteroaryl groupmay also be referred to as “aryl heterocycles” or “heteroaromatics”.“Heteroaryl” further encompasses polycyclic ring systems having two ormore rings in which two or more carbons are common to two adjoiningrings (i.e., “fused rings”) wherein at least one of the rings isheteroaromatic, e.g., the other cyclic ring or rings can be cycloalkyls,cycloalkenyls, cycloalkynyls, aryls, heterocycles, or combinationsthereof. Examples of heteroaryl rings include, but are not limited to,benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl,benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, furanyl,furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl,isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl,isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl,naphthyridinyl, octahydroisoquinolinyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl,pteridinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl,pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,tetrazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl and xanthenyl. One or moreof the rings can be substituted as defined below for “substitutedheteroaryl.”

The term “substituted heteroaryl” refers to a heteroaryl group in whichone or more hydrogen atoms on one or more heteroaromatic rings aresubstituted with one or more substituents including, but not limited to,halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl,alkoxy, carbonyl (such as a ketone, aldehyde, carboxyl, alkoxycarbonyl,formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as athioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl,phosphate, phosphonate, phosphinate, amino (or quarternized amino),amido, amidine, imine, cyano, nitro, azido, sulfhydryl, imino,alkylthio, sulfate, sulfonate, sulfamoyl, sulfoxide, sulfonamido,sulfonyl, heterocyclyl, alkylaryl, haloalkyl (such as CF₃, —CH₂—CF₃,—CCl₃), —CN, aryl, heteroaryl, and combinations thereof.

“Alkyl,” as used herein, refers to the radical of saturated aliphaticgroups, including straight-chain alkyl, alkenyl, or alkynyl groups,branched-chain alkyl, cycloalkyl (alicyclic), alkyl substitutedcycloalkyl groups, and cycloalkyl substituted alkyl. In preferredembodiments, a straight chain or branched chain alkyl has 30 or fewercarbon atoms in its backbone (e.g., C₁-C₃₀ for straight chains, C₃-C₃₀for branched chains), preferably 20 or fewer, more preferably 15 orfewer, most preferably 10 or fewer. Likewise, preferred cycloalkyls havefrom 3-10 carbon atoms in their ring structure, and more preferably have5, 6 or 7 carbons in the ring structure. The term “alkyl” (or “loweralkyl”) as used throughout the specification, examples, and claims isintended to include both “unsubstituted alkyls” and “substitutedalkyls,” the latter of which refers to alkyl moieties having one or moresubstituents replacing a hydrogen on one or more carbons of thehydrocarbon backbone. Such substituents include, but are not limited to,halogen, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl,or an acyl), thiocarbonyl (such as a thioester, a thioacetate, or athioformate), alkoxyl, phosphoryl, phosphate, phosphonate, a hosphinate,amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl,alkylthio, sulfate, sulfonate, sulfamoyl, sulfoxide, sulfonamido,sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromaticmoiety.

Unless the number of carbons is otherwise specified, “lower alkyl” asused herein means an alkyl group, as defined above, but having from oneto ten carbons, more preferably from one to six carbon atoms in itsbackbone structure. Likewise, “lower alkenyl” and “lower alkynyl” havesimilar chain lengths. Throughout the application, preferred alkylgroups are lower alkyls. In preferred embodiments, a substituentdesignated herein as alkyl is a lower alkyl.

“Alkyl” includes one or more substitutions at one or more carbon atomsof the hydrocarbon radical as well as heteroalkyls. Suitablesubstituents include, but are not limited to, halogens, such asfluorine, chlorine, bromine, or iodine; hydroxyl; —NRR′, wherein R andR′ are independently hydrogen, alkyl, or aryl, and wherein the nitrogenatom is optionally quaternized; —SR, wherein R is hydrogen, alkyl, oraryl; —CN; —NO₂; -COOH; carboxylate; —COR, —COOR, or —CON(R)₂ wherein Ris hydrogen, alkyl, or aryl; azide, aralkyl, alkoxyl, imino,phosphonate, phosphinate, silyl, ether, sulfonyl, sulfonamido,heterocyclyl, aromatic or heteroaromatic moieties, haloalkyl (such as—CF₃, —CH₂—CF₃, —CCl₃); —CN; —NCOCOCH₂CH₂; —NCOCOCHCH; —NCS; andcombinations thereof.

It will be understood by those skilled in the art that the moietiessubstituted on the hydrocarbon chain can themselves be substituted, ifappropriate. For instance, the substituents of a substituted alkyl mayinclude halogen, hydroxy, nitro, thiols, amino, azido, imino, amido,phosphoryl (including phosphonate and phosphinate), sulfonyl (includingsulfate, sulfonamido, sulfamoyl, sulfoxide and sulfonate), and silylgroups, as well as ethers, alkylthios, carbonyls (including ketones,aldehydes, carboxylates, and esters), haloalkyls, —CN and the like.Cycloalkyls can be substituted in the same manner.

The terms “alkenyl” and “alkynyl” refer to unsaturated aliphatic groupsanalogous in length and possible substitution to the alkyls describedabove, but that contain at least one double or triple bond respectively.

The term “substituted alkenyl” refers to alkenyl moieties having one ormore substituents replacing one or more hydrogen atoms on one or morecarbons of the hydrocarbon backbone. Such substituents include, but arenot limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl,cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl,formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as athioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl,phosphate, phosphonate, phosphinate, amino (or quarternized amino),amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio,sulfate, sulfonate, sulfamoyl, sulfoxide, sulfonamido, sulfonyl,heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, andcombinations thereof.

The term “substituted alkynyl” refers to alkynyl moieties having one ormore substituents replacing one or more hydrogen atoms on one or morecarbons of the hydrocarbon backbone. Such substituents include, but arenot limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl,cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxy carbonyl,formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as athioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl,phosphate, phosphonate, phosphinate, amino (or quarternized amino),amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio,sulfate, sulfonate, sulfamoyl, sulfoxide, sulfonamido, sulfonyl,heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, andcombinations thereof.

The term “phenyl” is art recognized, and refers to the aromatic moiety—C₆H₅, i.e., a benzene ring without one hydrogen atom.

The term “substituted phenyl” refers to a phenyl group, as definedabove, having one or more substituents replacing one or more hydrogenatoms on one or more carbons of the phenyl ring. Such substituentsinclude, but are not limited to, halogen, azide, alkyl, aralkyl,alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl,alkoxy carbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl(such as a thioester, a thioacetate, or a thioformate), alkoxyl,phosphoryl, phosphate, phosphonate, phosphinate, amino (or quarternizedamino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl,alkylthio, sulfate, sulfonate, sulfamoyl, sulfoxide, sulfonamido,sulfonyl, heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, andcombinations thereof.

“Amino” and “Amine,” as used herein, are art-recognized and refer toboth substituted and unsubstituted amines, e.g., a moiety that can berepresented by the general formula:

wherein, R, R′, and R″ each independently represent a hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbonyl, —(CH₂)_(m)—R″′, or R and R′ taken together withthe N atom to which they are attached complete a heterocycle having from3 to 14 atoms in the ring structure; R′″ represents a hydroxy group,substituted or unsubstituted carbonyl group, an aryl, a cycloalkyl ring,a cycloalkenyl ring, a heterocycle, or a poly cycle; and m is zero or aninteger ranging from 1 to 8. In preferred embodiments, only one of R andR′ can be a carbonyl, e.g., R and R′ together with the nitrogen do notform an imide. In preferred embodiments, R and R′ (and optionally R″)each independently represent a hydrogen atom, substituted orunsubstituted alkyl, a substituted or unsubstituted alkenyl, or—(CH₂)_(m)—R″′. Thus, the term ‘alkylamine’ as used herein refers to anamine group, as defined above, having a substituted or unsubstitutedalkyl attached thereto (i.e. at least one of R, R′, or R″ is an alkylgroup).

“Carbonyl,” as used herein, is art-recognized and includes such moietiesas can be represented by the general formula:

wherein X is a bond, or represents an oxygen or a sulfur, and Rrepresents a hydrogen, a substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted alkylaryl, substituted orunsubstituted arylalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, —(CH₂)_(m)—R″, or apharmaceutical acceptable salt, R′ represents a hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedalkylaryl, substituted or unsubstituted arylalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl or—(CH₂)_(m)—R″; R″ represents a hydroxy group, substituted orunsubstituted carbonyl group, an aryl, a cycloalkyl ring, a cycloalkenylring, a heterocycle, or a poly cycle; and m is zero or an integerranging from 1 to 8. Where X is oxygen and R is defines as above, themoiety is also referred to as a carboxyl group. When X is oxygen and Ris hydrogen, the formula represents a ‘carboxylic acid.’ Where X isoxygen and R′ is hydrogen, the formula represents a ‘formate.’ Where Xis oxygen and R or R′ is not hydrogen, the formula represents an“ester”. In general, where the oxygen atom of the above formula isreplaced by a sulfur atom, the formula represents a ‘thiocarbonyl’group. Where X is sulfur and R or R′ is not hydrogen, the formularepresents a ‘thioester.’ Where X is sulfur and R is hydrogen, theformula represents a ‘thiocarboxylic acid.’ Where X is sulfur and R′ ishydrogen, the formula represents a ‘thioformate.’ Where X is a bond andR is not hydrogen, the above formula represents a ‘ketone.’ Where X is abond and R is hydrogen, the above formula represents an ‘aldehyde.’

The term “substituted carbonyl” refers to a carbonyl, as defined above,wherein one or more hydrogen atoms in R, R′ or a group to which themoiety

is attached, are independently substituted. Such substituents include,but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl,alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl,alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl(such as a thioester, a thioacetate, or a thioformate), alkoxyl,phosphoryl, phosphate, phosphonate, phosphinate, amino (or quarternizedamino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl,alkylthio, sulfate, sulfonate, sulfamoyl, sulfoxide, sulfonamido,sulfonyl, heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, andcombinations thereof.

The term “carboxyl” is as defined above for the formula

and is defined more specifically by the formula —R^(iv)COOH, whereinR^(iv) is an alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,alkylaryl, arylalkyl, aryl, or heteroaryl. In preferred embodiments, astraight chain or branched chain alkyl, alkenyl, and alkynyl have 30 orfewer carbon atoms in its backbone (e.g., C₁-C₃₀ for straight chainalkyl, C₃-C₃₀ for branched chain alkyl, C₂-C₃₀ for straight chainalkenyl and alkynyl, C₃-C₃₀ for branched chain alkenyl and alkynyl),preferably 20 or fewer, more preferably 15 or fewer, most preferably 10or fewer. Likewise, preferred cycloalkyls, heterocyclyls, aryls andheteroaryls have from 3-10 carbon atoms in their ring structure, andmore preferably have 5, 6 or 7 carbons in the ring structure.

The term “substituted carboxyl” refers to a carboxyl, as defined above,wherein one or more hydrogen atoms in R^(iv) are substituted. Suchsubstituents include, but are not limited to, halogen, azide, alkyl,aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as acarboxyl, alkoxy carbonyl, formyl, or an acyl), silyl, ether, ester,thiocarbonyl (such as a thioester, a thioacetate, or a thioformate),alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (orquarternized amino), amido, amidine, imine, cyano, nitro, azido,sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfoxide,sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, —CN, aryl,heteroaryl, and combinations thereof.

“Heteroalkyl,” as used herein, refers to straight or branched chain, orcyclic carbon-containing radicals, or combinations thereof, containingat least one heteroatom.

Suitable heteroatoms include, but are not limited to, O, N, Si, P and S,wherein the nitrogen, phosphorous and sulfur atoms are optionallyoxidized, and the nitrogen heteroatom is optionally quaternized.

Examples of saturated hydrocarbon radicals include, but are not limitedto, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, andhomologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl,n-octyl. Examples of unsaturated alkyl groups include, but are notlimited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, and3-butynyl.

The terms “alkoxyl” or “alkoxy,” “aroxy” or “aryloxy,” generallydescribe compounds represented by the formula —OR^(v), wherein R^(v)includes, but is not limited to, substituted or unsubstituted alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkenyl,heterocycloalkenyl, aryl, heteroaryl, arylalkyl, heteroalkyls,alkylaryl, alkylheteroaryl.

The terms “alkoxyl” or “alkoxy” as used herein refer to an alkyl group,as defined above, having an oxygen radical attached thereto.Representative alkoxyl groups include methoxy, ethoxy, propyloxy,tert-butoxy and the like. An “ether” is two hydrocarbons covalentlylinked by an oxygen. Accordingly, the substituent of an alkyl thatrenders that alkyl an ether is or resembles an alkoxyl, such as can berepresented by one of —O-alkyl, —O-alkenyl, and —O-alkynyl. The termalkoxy also includes cycloalkyl, heterocyclyl, cycloalkenyl,heterocycloalkenyl, and arylalkyl having an oxygen radical attached toat least one of the carbon atoms, as valency permits.

The term “substituted alkoxy” refers to an alkoxy group having one ormore substituents replacing one or more hydrogen atoms on one or morecarbons of the alkoxy backbone. Such substituents include, but are notlimited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl,cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxy carbonyl,formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as athioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl,phosphate, phosphonate, phosphinate, amino (or quarternized amino),amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio,sulfate, sulfonate, sulfamoyl, sulfoxide, sulfonamido, sulfonyl,heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, andcombinations thereof.

The term “phenoxy” is art recognized, and refers to a compound of theformula —OR^(v) wherein R^(v) is (i.e., —O—C₆H₅). One of skill in theart recognizes that a phenoxy is a species of the aroxy genus.

The term “substituted phenoxy” refers to a phenoxy group, as definedabove, having one or more substituents replacing one or more hydrogenatoms on one or more carbons of the phenyl ring. Such substituentsinclude, but are not limited to, halogen, azide, alkyl, aralkyl,alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl,alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl(such as a thioester, a thioacetate, or a thioformate), alkoxyl,phosphoryl, phosphate, phosphonate, phosphinate, amino (or quarternizedamino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl,alkylthio, sulfate, sulfonate, sulfamoyl, sulfoxide, sulfonamido,sulfonyl, heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, andcombinations thereof.

The terms “aroxy” and “aryloxy,” as used interchangeably herein, arerepresented by —O-aryl or —O-heteroaryl, wherein aryl and heteroaryl areas defined herein.

The terms “substituted aroxy” and “substituted aryloxy,” as usedinterchangeably herein, represent —O-aryl or —O-heteroaryl, having oneor more substituents replacing one or more hydrogen atoms on one or morering atoms of the aryl and heteroaryl, as defined herein. Suchsubstituents include, but are not limited to, halogen, azide, alkyl,aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as acarboxyl, alkoxy carbonyl, formyl, or an acyl), silyl, ether, ester,thiocarbonyl (such as a thioester, a thioacetate, or a thioformate),alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (orquarternized amino), amido, amidine, imine, cyano, nitro, azido,sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfoxide,sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, —CN, aryl,heteroaryl, and combinations thereof.

The term “alkylthio” refers to an alkyl group, as defined above, havinga sulfur radical attached thereto. The “alkylthio” moiety is representedby —S-alkyl. Representative alkylthio groups include methylthio,ethylthio, and the like. The term “alkylthio” also encompassescycloalkyl groups having a sulfur radical attached thereto.

The term “substituted alkylthio” refers to an alkylthio group having oneor more substituents replacing one or more hydrogen atoms on one or morecarbon atoms of the alkylthio backbone. Such substituents include, butare not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl,cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl,formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as athioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl,phosphate, phosphonate, phosphinate, amino (or quarternized amino),amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio,sulfate, sulfonate, sulfamoyl, sulfoxide, sulfonamido, sulfonyl,heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, andcombinations thereof.

The term “phenylthio” is art recognized, and refers to —S—C₆H₅, i.e., aphenyl group attached to a sulfur atom.

The term “substituted phenylthio” refers to a phenylthio group, asdefined above, having one or more substituents replacing a hydrogen onone or more carbons of the phenyl ring. Such substituents include, butare not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl,cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxy carbonyl,formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as athioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl,phosphate, phosphonate, phosphinate, amino (or quarternized amino),amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio,sulfate, sulfonate, sulfamoyl, sulfoxide, sulfonamido, sulfonyl,heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, andcombinations thereof.

“Arylthio” refers to —S-aryl or —S-heteroaryl groups, wherein aryl andheteroaryl as as defined herein.

The term “substituted arylthio” represents —S-aryl or —S-heteroaryl,having one or more substituents replacing a hydrogen atom on one or morering atoms of the aryl and heteroaryl rings as defined herein. Suchsubstituents include, but are not limited to, halogen, azide, alkyl,aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as acarboxyl, alkoxy carbonyl, formyl, or an acyl), silyl, ether, ester,thiocarbonyl (such as a thioester, a thioacetate, or a thioformate),alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (orquarternized amino), amido, amidine, imine, cyano, nitro, azido,sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfoxide,sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, —CN, aryl,heteroaryl, and combinations thereof.

“Arylalkyl,” as used herein, refers to an alkyl group that issubstituted with a substituted or unsubstituted aryl or heteroarylgroup.

“Alkylaryl,” as used herein, refers to an aryl group (e.g., an aromaticor hetero aromatic group), substituted with a substituted orunsubstituted alkyl group.

The terms “amide” or “amido” are used interchangeably, refer to both“unsubstituted amido” and “substituted amido” and are represented by thegeneral formula:

wherein, E is absent, or E is substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted aralkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted aryl, substitutedor unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl,wherein independently of E, R and R′ each independently represent ahydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbonyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedalkylaryl, substituted or unsubstituted arylalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl,—(CH₂)_(m)—R″′, or R and R′ taken together with the N atom to which theyare attached complete a heterocycle having from 3 to 14 atoms in thering structure; R′″ represents a hydroxy group, substituted orunsubstituted carbonyl group, an aryl, a cycloalkyl ring, a cycloalkenylring, a heterocycle, or a poly cycle; and m is zero or an integerranging from 1 to 8. In preferred embodiments, only one of R and R′ canbe a carbonyl, e g., R and R′ together with the nitrogen do not form animide. In preferred embodiments, R and R′ each independently represent ahydrogen atom, substituted or unsubstituted alkyl, a substituted orunsubstituted alkenyl, or —(CH₂)_(m)—R″ When E is oxygen, a carbamate isformed. The carbamate cannot be attached to another chemical species,such as to form an oxygen-oxygen bond, or other unstable bonds, asunderstood by one of ordinary skill in the art.

The term “sulfonyl” is represented by the formula

wherein E is absent, or E is alkyl, alkenyl, alkynyl, aralkyl,alkylaryl, cycloalkyl, aryl, heteroaryl, heterocyclyl, whereinindependently of E, R represents a hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted amine,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted alkylaryl, substituted orunsubstituted arylalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, —(CH₂)_(m)—R″′, or E and Rtaken together with the S atom to which they are attached complete aheterocycle having from 3 to 14 atoms in the ring structure; R′″represents a hydroxy group, substituted or unsubstituted carbonyl group,an aryl, a cycloalkyl ring, a cycloalkenyl ring, a heterocycle, or apoly cycle; and m is zero or an integer ranging from 1 to 8. Inpreferred embodiments, only one of E and R can be substituted orunsubstituted amine, to form a “sulfonamide” or “sulfonamido.” Thesubstituted or unsubstituted amine is as defined above.

The term “substituted sulfonyl” represents a sulfonyl in which E and Rare independently substituted. Such substituents include, but are notlimited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl,cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl,formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as athioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl,phosphate, phosphonate, phosphinate, amino (or quarternized amino),amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio,sulfate, sulfonate, sulfamoyl, sulfoxide, sulfonamido, sulfonyl,heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, andcombinations thereof.

The term “sulfonic acid” refers to a sulfonyl, as defined above, whereinR is hydroxyl, and E is absent, or E is substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted alkylaryl, substituted or unsubstituted arylalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

The term “sulfate” refers to a sulfonyl, as defined above, wherein E isabsent, oxygen, alkoxy, aroxy, substituted alkoxy or substituted aroxy,as defined above, and R is independently hydroxyl, alkoxy, aroxy,substituted alkoxy or substituted aroxy, as defined above. When E isoxygen, the sulfate cannot be attached to another chemical species, suchas to form an oxygen-oxygen bond, or other unstable bonds, as understoodby one of ordinary skill in the art.

The term “sulfonate” refers to a sulfonyl, as defined above, wherein Eis oxygen, alkoxy, aroxy, substituted alkoxy or substituted aroxy, asdefined above, and R is independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted amine,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted alkylaryl, substituted orunsubstituted arylalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, —(CH₂)_(m)—R″′, R′″ representsa hydroxy group, substituted or unsubstituted carbonyl group, an aryl, acycloalkyl ring, a cycloalkenyl ring, a heterocycle, or a poly cycle;and m is zero or an integer ranging from 1 to 8. When E is oxygen,sulfonate cannot be attached to another chemical species, such as toform an oxygen-oxygen bond, or other unstable bonds, as understood byone of ordinary skill in the art.

The term “sulfamoyl” refers to a sulfonamide or sulfonamide representedby the formula

wherein E is absent, or E is substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted aralkyl, substituted orunsubstituted alkylaryl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocyclyl, whereinindependently of E, R and R′ each independently represent a hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbonyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedalkylaryl, substituted or unsubstituted arylalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl,—(CH₂)_(m)—R″′, or R and R′ taken together with the N atom to which theyare attached complete a heterocycle having from 3 to 14 atoms in thering structure; R′″ represents a hydroxy group, substituted orunsubstituted carbonyl group, an aryl, a cycloalkyl ring, a cycloalkenylring, a heterocycle, or a poly cycle; and m is zero or an integerranging from 1 to 8. In preferred embodiments, only one of R and R′ canbe a carbonyl, e.g., R and R′ together with the nitrogen do not form animide.

The term “sulfoxide” is represented by the formula

wherein E is absent, or E is alkyl, alkenyl, alkynyl, aralkyl,alkylaryl, cycloalkyl, aryl, heteroaryl, heterocyclyl, whereinindependently of E, R represents a hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted amine,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted alkylaryl, substituted orunsubstituted arylalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, —(CH₂)_(m)—R″′, or E and Rtaken together with the S atom to which they are attached complete aheterocycle having from 3 to 14 atoms in the ring structure; R′″represents a hydroxy group, substituted or unsubstituted carbonyl group,an aryl, a cycloalkyl ring, a cycloalkenyl ring, a heterocycle, or apoly cycle; and m is zero or an integer ranging from 1 to 8.

The term “phosphonyl” is represented by the formula

wherein E is absent, or E is substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted aralkyl, substituted orunsubstituted alkylaryl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocyclyl, wherein,independently of E, R^(vi) and R^(vii) are independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbonyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedalkylaryl, substituted or unsubstituted arylalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl,—(CH₂)_(m)—R″′, or R and R′ taken together with the P atom to which theyare attached complete a heterocycle having from 3 to 14 atoms in thering structure; R′″ represents a hydroxy group, substituted orunsubstituted carbonyl group, an aryl, a cycloalkyl ring, a cycloalkenylring, a heterocycle, or a poly cycle; and m is zero or an integerranging from 1 to 8.

The term “substituted phosphonyl” represents a phosphonyl in which E,R^(vi) and R^(vii) are independently substituted. Such substituentsinclude, but are not limited to, halogen, azide, alkyl, aralkyl,alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl,alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl(such as a thioester, a thioacetate, or a thioformate), alkoxyl,phosphoryl, phosphate, phosphonate, phosphinate, amino (or quarternizedamino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl,alkylthio, sulfate, sulfonate, sulfamoyl, sulfoxide, sulfonamido,sulfonyl, heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, andcombinations thereof.

The term “phosphoryl” defines a phoshonyl in which E is absent, oxygen,alkoxy, aroxy, substituted alkoxy or substituted aroxy, as definedabove, and independently of E, R^(vi) and R^(vii) are independentlyhydroxyl, alkoxy, aroxy, substituted alkoxy or substituted aroxy, asdefined above. When E is oxygen, the phosphoryl cannot be attached toanother chemical species, such as to form an oxygen-oxygen bond, orother unstable bonds, as understood by one of ordinary skill in the art.When E, R^(vi) and R^(vii) are substituted, the substituents include,but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl,alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (suchas a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl,phosphate, phosphonate, phosphinate, amino (or quarternized amino),amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio,sulfate, sulfonate, sulfamoyl, sulfoxide, sulfonamido, sulfonyl,heterocyclyl, alkylaryl, haloalkyl, —CN, aryl, heteroaryl, andcombinations thereof.

The term “polyaryl” refers to a chemical moiety that includes two ormore aryls, heteroaryls, and combinations thereof. The aryls,heteroaryls, and combinations thereof, are fused, or linked via a singlebond, ether, ester, carbonyl, amide, sulfonyl, sulfonamide, alkyl, azo,and combinations thereof.

The term “substituted polyaryl” refers to a polyaryl in which one ormore of the aryls, heteroaryls are substituted, with one or moresubstituents including, but not limited to, halogen, azide, alkyl,aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as acarboxyl, alkoxy carbonyl, formyl, or an acyl), silyl, ether, ester,thiocarbonyl (such as a thioester, a thioacetate, or a thioformate),alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (orquarternized amino), amido, amidine, imine, cyano, nitro, azido,sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfoxide,sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, —CN, aryl,heteroaryl, and combinations thereof.

The term “C₃-C₂₀ cyclic” refers to a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted cycloalkenyl, substituted orunsubstituted cycloalkynyl, substituted or unsubstituted heterocyclylthat have from three to 20 carbon atoms, as geometric constraintspermit. The cyclic structures are formed from single or fused ringsystems. The substituted cycloalkyls, cycloalkenyls, cycloalkynyls andheterocyclyls are substituted as defined above for the alkyls, alkenyls,alkynyls and heterocyclyls, respectively.

The terms “hydroxyl” and “hydroxy” are used interchangeably and arerepresented by —OH.

The terms “thiol” and “sulfhydryl” are used interchangeably and arerepresented by —SH.

The term “oxo” refers to ═O bonded to a carbon atom.

The terms “cyano” and “nitrile” are used interchangeably to refer to—CN.

The term “nitro” refers to —NO₂.

The term “phosphate” refers to —O—PO₃.

The term “azide” or “azido” are used interchangeably to refer to —N₃.

The term “substituted C₁-C_(x) alkyl” refers to alkyl groups having fromone to x carbon atoms, wherein at least one carbon atom is substituted,wherein “x” is an integer from one and ten. The term “unsubstitutedC₁-C_(x) alkyl” refers to alkyl groups having from one to x carbon atomsthat are not substituted, wherein “x” is an integer from one to ten.

The term “substituted C₁-C_(x) alkylene” refers to alkylene groupshaving from one to x carbon atoms, wherein at least one carbon atom issubstituted, wherein “x” is an integer from one to ten. The term“unsubstituted C₁-C_(x) alkylene” refers to alkylene groups having fromone to x carbon atoms that are not substituted, wherein “x” is aninteger from one to ten. The term “alkylene” as used herein, refers to amoiety with the formula —(CH₂)_(a)—, wherein “a” is an integer from oneto 10.

The term “substituted C₂-C_(x) alkenyl” refers to alkenyl groups havingfrom two to x carbon atoms, wherein at least one carbon atom issubstituted, wherein “x” is an integer from two to ten. The term“unsubstituted C₂-C_(x) alkenyl” refers to alkenyl groups having fromtwo to x carbon atoms that are not substituted, wherein “x” is aninteger from two to ten.

The term “substituted C₂-C_(x) alkynyl” refers to alkynyl groups havingfrom two to x carbon atoms, wherein at least one carbon atom issubstituted, wherein “x” is an integer from two to ten. The term“unsubstituted C₂-C_(x) alkynyl” refers to alkynyl groups having fromtwo to x carbon atoms that are not substituted, wherein “x” is aninteger from two to ten.

The term “substituted C₁-C_(x) alkoxy” refers to alkoxy groups havingfrom one to x carbon atoms, wherein at least one carbon atom issubstituted, wherein “x” is an integer from one to ten. The term“unsubstituted C₁-C_(x) alkoxy” refers to alkoxy groups having from oneto x carbon atoms that are not substituted, wherein “x” is an integerfrom one to ten.

The term “substituted C₁-C_(x) alkylamino” refers to alkylamino groupshaving from one to x carbon atoms, wherein at least one carbon atom issubstituted, wherein “x” is an integer from one to ten. The term“unsubstituted C₁-C_(x) alkylamino” refers to alkylamino groups havingfrom one to x carbon atoms that are not substituted, wherein “x” is aninteger from one to ten. The terms “alkylamine” and “alkylamino” areused interchangeably. In any alkylamino, where the nitrogen atom issubstituted with one, two, or three substituents, the nitrogen atom canbe referred to as a secondary, tertiary, or quaternary nitrogen atom,respectively.

The term “substituted C₁-C_(x) alkylthio” refers to alkylthio groupshaving from one to x carbon atoms, wherein at least one carbon atom issubstituted, wherein “x” is an integer from one to ten. The term“unsubstituted C₁-C_(x) alkylthio” refers to alkylthio groups havingfrom one to x carbon atoms that are not substituted, wherein “x” is aninteger from one to ten.

The term “substituted C₁-C_(x) carbonyl” refers to carbonyl groupshaving from one to x carbon atoms, wherein at least one carbon atom issubstituted, wherein “x” is an integer from one to ten. The term“unsubstituted C₁-C_(x) carbonyl” refers to carbonyl groups having fromone to x carbon atoms that are not substituted, wherein “x” is aninteger from one to ten.

The term “substituted C₁-C_(x) carboxyl” refers to carboxyl groupshaving from one to x carbon atoms, wherein at least one carbon atom issubstituted, wherein “x” is an integer from one to ten. The term“unsubstituted C₁-C_(x) carboxyl” refers to carboxyl groups having fromone to x carbon atoms that are not substituted, wherein “x” is aninteger from one to ten.

The term “substituted C₁-C_(x) amido” refers to amido groups having fromone to x carbon atoms, wherein at least one carbon atom is substituted,wherein “x” is an integer from one to ten. The term “unsubstitutedC₁-C_(x) amido” refers to amido groups having from one to x carbon atomsthat are not substituted, wherein “x” is an integer from one to ten.

The term “substituted C₁-C_(x) sulfonyl” refers to sulfonyl groupshaving from one to x carbon atoms, wherein at least one carbon atom issubstituted, wherein “x” is an integer from one to ten. The term“unsubstituted C₁-C_(x) sulfonyl” refers to sulfonyl groups having fromone to x carbon atoms that are not substituted, wherein “x” is aninteger from one to ten.

The term “substituted C₁-C_(x) sulfonic acid” refers to sulfonic acidgroups having from one to x carbon atoms, wherein at least one carbonatom is substituted, wherein “x” is an integer from one to ten. The term“unsubstituted C₁-C_(x) sulfonic acid” refers to sulfonic acid groupshaving from one to x carbon atoms that are not substituted, wherein “x”is an integer from one to ten.

The term “substituted C₁-C_(x) sulfamoyl” refers to sulfamoyl groupshaving from one to x carbon atoms, wherein at least one carbon atom issubstituted, wherein “x” is an integer from one to ten. The term“unsubstituted C₁-C_(x) sulfamoyl” refers to sulfamoyl groups havingfrom one to x carbon atoms that are not substituted, wherein “x” is aninteger from one to ten.

The term “substituted C₁-C_(x) sulfoxide” refers to sulfoxide groupshaving from one to x carbon atoms, wherein at least one carbon atom issubstituted, wherein “x” is an integer from one to ten. The term“unsubstituted C₁-C_(x) sulfoxide” refers to sulfoxide groups havingfrom one to x carbon atoms that are not substituted, wherein “x” is aninteger from one to ten.

The term “substituted C₁-C_(x) phosphoryl” refers to phosphoryl groupshaving from one to x carbon atoms, wherein at least one carbon atom issubstituted, wherein “x” is an integer from one to ten. The term“unsubstituted C₁-C_(x) phosphoryl” refers to phosphoryl groups havingfrom one to x carbon atoms that are not substituted, wherein “x” is aninteger from one to ten.

The term “substituted C₁-C_(x) phosphonyl” refers to phosphonyl groupshaving from one to x carbon atoms, wherein at least one carbon atom issubstituted, wherein “x” is an integer from one to ten. The term“unsubstituted C₁-C_(x) phosphonyl” refers to phosphonyl groups havingfrom one to x carbon atoms that are not substituted, wherein “x” is aninteger from one to ten.

The term “substituted C₀-C_(x) sulfonyl” refers to sulfonyl groupshaving from zero to x carbon atoms, wherein at least one carbon atom issubstituted, wherein “x” is an integer from zero to ten. The term“unsubstituted C₀-C_(x) sulfonyl” refers to sulfonyl groups having fromzero to ten carbon atoms that are not substituted, wherein “x” is aninteger from zero to ten.

The term “substituted C₀-C_(x) sulfonic acid” refers to sulfonic acidgroups having from zero to ten carbon atoms, wherein at least one carbonatom is substituted, wherein “x” is an integer from zero to ten. Theterm “unsubstituted C₀-C_(x) sulfonic acid” refers to sulfonic acidgroups having from zero to ten carbon atoms that are not substituted,wherein “x” is an integer from zero to ten.

The term “substituted C₀-C_(x) sulfamoyl” refers to sulfamoyl groupshaving from zero to ten carbon atoms, wherein at least one carbon atomis substituted, wherein “x” is an integer from zero to ten. The term“unsubstituted C₀-C_(x) sulfamoyl” refers to alkenyl groups having fromtwo to nine carbon atoms that are not substituted, wherein “x” is aninteger from zero to ten.

The term “substituted C₀-C_(x) sulfoxide” refers to sulfoxide groupshaving from zero to ten carbon atoms, wherein at least one carbon atomis substituted, wherein “x” is an integer from zero to ten. The term“unsubstituted C₀-C_(x) sulfoxide” refers to sulfoxide groups havingfrom two to nine carbon atoms that are not substituted, wherein “x” isan integer from zero to ten.

The term “substituted C₀-C_(x) phosphoryl” refers to phosphoryl groupshaving from zero to ten carbon atoms, wherein at least one carbon atomis substituted, wherein “x” is an integer from zero to ten. The term“unsubstituted C₀-C_(x) phosphoryl” refers to phosphoryl groups havingfrom zero to ten carbon atoms that are not substituted, wherein “x” isan integer from zero to ten.

The term “substituted C₀-C_(x) phosphonyl” refers to phosphonyl groupshaving from zero to x carbon atoms, wherein at least one carbon atom issubstituted, wherein “x” is an integer from zero to ten. The term“unsubstituted C₀-C_(x) phosphonyl” refers to phosphonyl groups havingfrom zero to x carbon atoms that are not substituted, wherein “x” is aninteger from zero to ten.

The terms substituted “C_(x) alkyl,” “C_(x) alkylene,” “C_(x) alkenyl,”“C_(x) alkynyl,” “C_(x) alkoxy,” “C_(x) alkylamino,” “C_(x) alkylthio,”“C_(x) carbonyl,” “C_(x) carboxyl,” “C_(x) amido,” “C_(x) sulfonyl,”“C_(x) sulfonic acid,” “C_(x) sulfamoyl,” “C_(x) phosphoryl,” and “C_(x)phosphonyl” refer to alkyl, alkylene, alkenyl, alkynyl, alkoxy,alkylamino, alkylthio, carbonyl, carboxyl, amido, sulfonyl, sulfonicacid, sulfamoyl, sulfoxide, phosphoryl, and phosphonyl groups,respectively, having x carbon atoms, wherein at least one carbon atom issubstituted, wherein x is an integer from one to ten. The termsunsubstituted “C_(x) alkyl,” “C_(x) alkylene,” “C_(x) alkenyl,” “C_(x)alkynyl,” “C_(x) alkoxy,” “C_(x) alkylamino”, “C_(x) alkylthio,” “C_(x)carbonyl,” “C_(x) carboxyl,” “C_(x) amido,” “C_(x) sulfonyl,” “C_(x)sulfonic acid,” “C_(x) sulfamoyl,” “C_(x) phosphoryl,” and “C_(x)phosphonyl” refer to alkyl, alkylene, alkenyl, alkynyl, alkoxy,alkylamino, alkylthio, carbonyl, carboxyl, amido, sulfonyl, sulfonicacid, sulfamoyl, sulfoxide, phosphoryl, and phosphonyl groups,respectively, having x carbon atoms that are not substituted, wherein xis an integer from one to ten.

The terms unsubstituted “C₀ sulfonyl,” “C₀ sulfonic acid,” “C₀sulfamoyl,” “C₀ phosphoryl,” and “C₀ phosphonyl” refer to alkyl,alkylene, alkenyl, alkynyl, alkoxy, alkylamino, alkylthio, carbonyl,carboxyl, amido, sulfonyl, sulfonic acid, sulfamoyl, sulfoxide,phosphoryl, and phosphonyl groups, respectively, having zero carbonatoms that are not substituted.

“Halogen,” as used herein, refers to fluorine, chlorine, bromine, oriodine.

As used herein, U₁, represents the organic groups alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, arylalkyl, substituted arylalkyl, alkoxy,substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substitutedaroxy, alkylthio, substituted alkylthio, phenylthio, substitutedphenylthio, arylthio, substituted arylthio, carbonyl, substitutedcarbonyl, carboxyl, substituted carboxyl, amino, substituted amino,amido, substituted amido, poly aryl, substituted poly aryl, C₃-C₂₀cyclic, substituted C₃-C₂₀ cyclic, heterocyclic, substitutedheterocyclic, amino acid, poly(ethylene glycol), peptide, andpolypeptide group.

As used herein, U₂ represents the organic groups alkylamino,dialkylamino, hydroxy, alkenyl, alkynyl, substituted alkyl, substitutedalkenyl, substituted alkynyl, phenyl, substituted phenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, alkoxy,substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substitutedaroxy, alkylthio, substituted alkylthio, phenylthio, substitutedphenylthio, arylthio, substituted arylthio, carbonyl, substitutedcarbonyl, carboxyl, substituted carboxyl, amino, substituted amino,amido, substituted amido, polyaryl, substituted polyaryl, C₃-C₂₀ cyclic,substituted C₃-C₂₀ cyclic, heterocyclic, substituted heterocyclic, aminoacid, poly(ethylene glycol), and polypeptide group.

As used herein, U₃ represents the organic groups alkylamino,dialkylamino, hydroxy, alkyl, alkenyl, alkynyl, substituted alkyl,substituted alkenyl, substituted alkynyl, phenyl, substituted phenyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy,substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substitutedaroxy, alkylthio, substituted alkylthio, phenylthio, substitutedphenylthio, arylthio, substituted arylthio, carbonyl, substitutedcarbonyl, carboxyl, substituted carboxyl, amino, substituted amino,amido, substituted amido, polyaryl, substituted polyaryl, C₃-C₂₀ cyclic,substituted C₃-C₂₀ cyclic, heterocyclic, substituted heterocyclic, aminoacid, poly(ethylene glycol), peptide, and polypeptide group.

As used herein, U₄ represents the organic groups alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, alkoxy,substituted alkoxy, carboxyl, substituted carboxyl, amino, substitutedamino, amido, substituted amido, C₃-C₂₀ cyclic, substituted C₃-C₂₀cyclic, heterocyclic, and substituted heterocyclic.

As used herein, Q₁ represents the organic groups arylalkyl andsubstituted arylalkyl.

As used herein, Q₂ represents the organic groups sulfonyl, substitutedsulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl,and substituted phosphonyl.

As used herein, Q₃ represents the organic group poly(lactic-co-glycolicacid).

As used herein, Q₄ represents organic groups substituted alkylene andunsubstituted alkylene.

As used herein, Q₅ represents the organic groups alkylamino,dialkylamino, and hydroxy.

As used herein, Q₆ represents the organic groups aroxy, substitutedaroxy, carbonyl, substituted carbonyl, and poly(ethylene glycol).

As used herein, Q₇ represents the organic groups alkylthio, substitutedalkylthio, arylthio, substituted arylthio, phenoxy, substituted phenoxy,phenylthio, substituted phenylthio, polyaryl, and substituted polyaryl.

As used herein, Q₈ represents the organic groups amino acid, peptide,and polypeptide group.

As used herein, Q₉ represents the organic groups phenyl and substitutedphenyl.

In some embodiments, groups Q₁; Q₂, Q₃, Q₄, or any combination thereof,can be used along with any one of U₁; U₂, and U₃. For example, U₁ can becombined with Q₁, with Q₂, with Q₃, with Q₄, with Q₁ and Q₂, with Q₁ andQ₃, with Q₁ and Q₄, with Q₂ and Q₃, with Q₂ and Q₄, with Q₃, and Q₄,with Q₁; Q₂, and Q₃, with Q₁; Q₂, and Q₄, with Q₁; Q₃, and Q₄, with Q₂,Q₃, and Q₄, and with with Q₁; Q₂, Q₃, and Q₄. Such combinations arereferred to as U₁+Q₁; U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄,U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄,U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, respectively. Similarly, U₂ can becombined with Q₁, with Q₂, with Q₃, with Q₄, with Q₁ and Q₂, with Q₁ andQ₃, with Q₁ and Q₄, with Q₂ and Q₃, with Q₂ and Q₄, with Q₃, and Q₄,with Q₁; Q₂, and Q₃, with Q₁; Q₂, and Q₄, with Q₁; Q₃, and Q₄, with Q₂,Q₃, and Q₄, and with with Q₁, Q₂, Q₃, and Q₄. Such combinations arereferred to as U₂+Q₁; U₂+Q₂, U₂+Q₃, U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄,U₂+Q₂+Q₃, U₂+Q₂+Q₄, U₂+Q₃+Q₄, U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄,U₂+Q₂+Q₃+Q₄, and U₂+Q₁+Q₂+Q₃+Q₄, respectively. Similarly, U₃ can becombined with Q₁; with Q₂, with Q₃, with Q₄, with Q₁ and Q₂, with Q₁ andQ₃, with Q₁ and Q₄, with Q₂ and Q₃, with Q₂ and Q₄, with Q₃, and Q₄,with Q₁; Q₂, and Q₃, with Q₁; Q₂, and Q₄, with Q₁; Q₃, and Q₄, with Q₂,Q₃, and Q₄, and with with Q₁; Q₂, Q₃, and Q₄. Such combinations arereferred to as U₃+Q₁; U₃+Q₂, U₃+Q₃, U₃+Q₄, U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄,U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃, U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄,U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄, respectively.

In some embodiments, groups Q₁; Q₂, Q₃, Q₄, Q₅, or any combinationthereof, can be used along with 1% For example, U₁ can be combined withQ₁, with Q₂, with Q₃, with Q₄, with Q₅, with Q₁ and Q₂, with Q₁ and Q₃,with Q₁ and Q₄, with Q₁ and Q₅, with Q₂ and Q₃, with Q₂ and Q₄, with Q₂and Q₅, with Q₃ and Q₄, with Q₃ and Q₅, with Q₄ and Q₅, with Q_(b) Q₂,and Q₃, with Q₁; Q₂, and Q₄, with Q₁; Q₂, and Q₅, with Q₁; Q₃, and Q₄,with Q₁, Q₃, and Q₅, with Q₁; Q₄, and Q₅, with Q₂, Q₃, and Q₄, with Q₂,Q₃, and Q₅, with Q₂, Q₄, and Q₅, with Q₃, Q₄, and Q₅, with Q₁; Q₂, Q₃,and Q₄, with Q₁; Q₂, Q₃, and Q₅, with Q_(b) Q₂, Q₄, and Q₅, with Q₁; Q₃,Q₄, and Q₅, with Q₂, Q₃, Q₄, and Q₅, with Q₁; Q₂, Q₃, Q₄, and Q₅. Suchcombinations can be referred to as U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₅,U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₁+Q₅, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₂+Q₅,U₁+Q₃+Q₄, U₁+Q₃+Q₅, U₁+Q₄+Q₅, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₂+Q₅,U₁+Q₁+Q₃+Q₄, U₁+Q₁+Q₃+Q₅, U₁+Q₁+Q₄+Q₅, U₁+Q₂+Q₃+Q₄, U₁+Q₂+Q₃+Q₅,U₁+Q₂+Q₄+Q₅, U₁+Q₃+Q₄+Q₅, U₁+Q₁+Q₂+Q₃+Q₄, U₁+Q₁+Q₂+Q₃+Q₅,U₁+Q₁+Q₂+Q₄+Q₅, U₁+Q₁+Q₃+Q₄+Q₅, U₁+Q₂+Q₃+Q₄+Q₅, U₁+Q₁+Q₂+Q₃+Q₄, +Q8,respectively.

In some embodiments, groups Q₁, Q₂, Q₃, Q₄, Q₅, Q₆, Q₇, Q₈, Q₉ or anycombination thereof, can be used along with U₄. For example, U₄ can becombined with Q₁, with Q₂, with Q₃, with Q₄, with Q₅, with Q₆, with Q₇,with Q₈, with Q₉, with Q₁+Q₂, with Q₁+Q₃, with Q₁+Q₄, with Q₁+Q₅, withQ₁+Q₆, with Q₁+Q₇, with Q₁+Q₈, with Q₁+Q₉, with Q₂+Q₃, with Q₂+Q₄, withQ₂+Q₅, with Q₂+Q₆, with Q₂+Q₇, with Q₂+Q₈, with Q₂+Q₉, with Q₃+Q₄, withQ₃+Q₅, with Q₃+Q₆, with Q₃+Q₇, with Q₃+Q₈, with Q₃+Q₉, with Q₄+Q₅, withQ₄+Q₆, with Q₄+Q₇, with Q₄+Q₈, with Q₄+Q₉, with Q₅+Q₆, with Q₅+Q₇, withQ₅+Q₈, with Q₅+Q₉, with Q₆+Q₇, with Q₆+Q₈, with Q₆+Q₉, with Q₇+Q₈, withQ₇+Q₉, with Q₈+Q₉, with Q₁+Q₂+Q₃, with Q₁+Q₂+Q₄, with Q₁+Q₂+Q₅, withQ₁+Q₂+Q₆, with Q₁+Q₂+Q₇, with Q₁+Q₂+Q8, with Q₁+Q₂+Q₉, with Q₁+Q₃+Q₄,with Q₁+Q₃+Q₅, with Q₁+Q₃+Q₆, with Q₁+Q₃+Q₇, with Q₁+Q₃+Q₈, withQ₁+Q₃+Q₉, with Q₁+Q₄+Q₅, with Q₁+Q₄+Q₆, with Q₁+Q₄+Q₇, with Q₁+Q₄+Q₈,with Q₁+Q₄+Q₉, with Q₁+Q₅+Q₉, with Q₁+Q₅+Q₇, with Q₁+Q₅+Q₈, withQ₁+Q₅+Q₉, with Q₂+Q₃+Q₇, with Q₁+Q₆+Q₈, with Q₁+Q₆+Q₉, with Q₁+Q₇+Q₈,with Q₁+Q₇+Q₉, with Q₁+Q₈+Q₉, with Q₂+Q₃+Q₄, with Q₂+Q₃+Q₅, withQ₂+Q₃+Q₆, with Q₂+Q₃+Q₇, with Q₂+Q₃+Q₈, with Q₂+Q₃+Q₉, with Q₂+Q₄+Q₅,with Q₂+Q₄+Q₆, with Q₂+Q₄+Q₇, with Q₂+Q₄+Q₈, with Q₂+Q₄+Q₉, withQ₂+Q₅+Q₆, with Q₂+Q₅+Q₇, with Q₂+Q₈+Q₈, with Q₂+Q₅+Q₉, with Q₂+Q₆+Q₇,with Q₂+Q₆+Q₈, with Q₂+Q₆+Q₉, with Q₂+Q₇+Q₈, with Q₂+Q₇+Q₉, withQ₂+Q₈+Q₉, with Q₃+Q₄+Q₅, with Q₃+Q₄+Q₆, with Q₃+Q₄+Q₇, with Q₃+Q₄+Q₈,with Q₃+Q₄+Q₉, with Q₃+Q₅+Q₆, with Q₃+Q₅+Q₇, with Q₃+Q₅+Q₈, withQ₃+Q₅+Q₉, with Q₃+Q₆+Q₇, with Q₃+Q₃+Q₈, with Q₃+Q₆+Q₉, with Q₃+Q₇+Q₈,with Q₃+Q₇+Q₉, with Q₃+Q₈+Q₉, with Q₄+Q₅+Q₉, with Q₄+Q₅+Q₇, withQ₄+Q₅+Q₈, with Q₄+Q₅+Q₉, with Q₄+Q₆+Q₇, with Q₄+Q₆+Q₈, with Q₄+Q₆+Q₉,with Q₄+Q₇+Q₈, with Q₄+Q₇+Q₉, with Q₄+Q₈+Q₉, with Q₅+Q₃+Q₇, withQ₅+Q₃+Q₈, with Q₅+Q₃+Q₉, with Q₅+Q₇+Q₈, with Q₅+Q₇+Q₉, with Q₅+Q₈+Q₉,with Q₆+Q₇+Q₈, with Q₆+Q₇+Q₉, with Q₃+Q₈+Q₉, with Q₁+Q₂+Q₃+Q₄, withQ₁+Q₂+Q₃+Q₅, with Q₁+Q₂+Q₃+Q₆, with Q₁+Q₂+Q₃+Q₇, with Q₁+Q₂+Q₃+Q₈, withQ₁+Q₂+Q₃+Q₉, with Q₁+Q₃+Q₄+Q₈, with Q₁+Q₃+Q₄+Q₆, with Q₁+Q₃+Q₄+Q₇, withQ₁+Q₃+Q₄+Q₈, with Q₁+Q₃+Q₄+Q₉, with Q₁+Q₄+Q₅+Q₉, with Q₁+Q₄+Q₅+Q₇, withQ_(x)+Q₄+Q₅+Q₈, with Q₁+Q₄+Q₅+Q₉, with Q₁+Q₅+Q₆+Q₇, with Q₁+Q₅+Q₆+Q₈,with Q₁+Q₅+Q₃+Q₉, with Q₁+Q₆+Q₇+Q₈, with Q₁+Q₆+Q₇+Q₉, withQ_(x)+Q₇+Q₈+Q₉, with Q₂+Q₃+Q₄+Q₈, with Q₂+Q₃+Q₄+Q₆, with Q₂+Q₃+Q₄+Q₇,with Q₂+Q₃+Q₄+Q₈, with Q₂+Q₃+Q₄+Q₉, with Q₂+Q₄+Q₅+Q₉, with Q₂+Q₄+Q₅+Q₇,with Q₂+Q₄+Q₅+Q₈, with Q₂+Q₄+Q₅+Q₉, with Q₂+Q₅+Q₆+Q₇, with Q₂+Q₅+Q₃+Q₈,with Q₂+Q₅+Q₃+Q₉, with Q₂+Q₆+Q₇+Q₈, with Q₂+Q₆+Q₇+Q₉, with Q₂+Q₇+Q₈+Q₉,with Q₃+Q₄+Q₅+Q₆, with Q₃+Q₄+Q₅+Q₇, with Q₃+Q₄+Q₅+Q₈, with Q₃+Q₄+Q₅+Q₉,with Q₃+Q₅+Q₃+Q₇, with Q₃+Q₅+Q₆+Q₈, with Q₃+Q₅+Q₃+Q₉, with Q₃+Q₆+Q₇+Q₈,with Q₃+Q₆+Q₇+Q₉, with Q₃+Q₇+Q₈+Q₉, with Q₄+Q₅+Q₃+Q₇, with Q₄+Q₅+Q₃+Q₈,with Q₄+Q₅+Q₆+Q₉, with Q₄+Q₃+Q₇+Q₈, with Q₄+Q₆+Q₇+Q₉, with Q₄+Q₇+Q₈+Q₉,with Q₅+Q₃+Q₇+Q₈, with Q₅+Q₃+Q₇+Q₉, with Q₅+Q₇+Q₈+Q₉, withQ_(x)+Q₂+Q₃+Q₄+Q₅, with Q₁+Q₂+Q₃+Q₄+Q₆, with Q₁+Q₂+Q₃+Q₄+Q₇, withQ₄+Q₂+Q₃+Q₄+Q₈, with Q₁+Q₂+Q₃+Q₄+Q₉, with Q₁+Q₃+Q₄+Q₅+Q₆, withQ₁+Q₃+Q₄+Q₅+Q₇, with Q₁+Q₃+Q₄+Q₅+Q₈, with Q₁+Q₃+Q₄+Q₅+Q₉, withQ₁+Q₄+Q₈+Q₆+Q₇, with Q₁+Q₄+Q₅+Q₆+Q₈, with Q₁+Q₄+Q₅+Q₆+Q₉, withQ₁+Q₅+Q₆+Q₇+Q₈, with Q₁+Q₅+Q₆+Q₇+Q₉, with Q₁+Q₆+Q₇+Q₈+Q₉, withQ₂+Q₃+Q₄+Q₈+Q₉, with Q₂+Q₃+Q₄+Q₅+Q₇, with Q₂+Q₃+Q₄+Q₅+Q₈, withQ₂+Q₃+Q₄+Q₈+Q₉, with Q₂+Q₄+Q₅+Q₆+Q₇, with Q₂+Q₄+Q₅+Q₆+Q₈, withQ₂+Q₄+Q₈+Q₆+Q₉, with Q₂+Q₅+Q₆+Q₇+Q₈, with Q₂+Q₅+Q₆+Q₇+Q₉, withQ₂+Q₆+Q₇+Q₈+Q₉, with Q₃+Q₄+Q₅+Q₆+Q₇, with Q₃+Q₄+Q₅+Q₃+Q₈, withQ₃+Q₄+Q₅+Q₆+Q₉, with Q₃+Q₅+Q₆+Q₇+Q₈, with Q₃+Q₅+Q₆+Q₇+Q₉, withQ₃+Q₆+Q₇+Q₈+Q₉, with Q₄+Q₅+Q₆+Q₇+Q₈, with Q₄+Q₅+Q₆+Q₇+Q₉, withQ₄+Q₆+Q₇+Q₈+Q % with Q₅+Q₆+Q₇+Q₈+Q₉, with Q₁+Q₂+Q₃+Q₄+Q₅+Q₆, withQ₁+Q₂+Q₃+Q₄+Q₈+Q₇, with Q₁+Q₂+Q₃+Q₄+Q₅+Q₈, with Q₁+Q₂+Q₃+Q₄+Q₅+Q₉, withQ₁+Q₃+Q₄+Q₅+Q₆+Q₇, with Q₁+Q₃+Q₄+Q₈+Q₆+Q₈, with Q₁+Q₃+Q₄+Q₅+Q₆+Q₉, withQ₁+Q₄+Q₅+Q₆+Q₇+Q₈, with Q₁+Q₄+Q₅+Q₆+Q₇+Q₉, with Q₁+Q₅+Q₆+Q₇+Q₈+Q₉, withQ₂+Q₃+Q₄+Q₈+Q₆+Q₇, with Q₂+Q₃+Q₄+Q₈+Q₆+Q₈, with Q₂+Q₃+Q₄+Q₈+Q₆+Q₉, withQ₂+Q₄+Q₈+Q₆+Q₇+Q₈, with Q₂+Q₄+Q₅+Q₆+Q₇+Q₉, with Q₂+Q₅+Q₆+Q₇+Q₈+Q₉, withQ₃+Q₄+Q₅+Q₆+Q₇+Q₈, with Q₃+Q₄+Q₅+Q₆+Q₇+Q₉, with Q₃+Q₅+Q₆+Q₇+Q₈+Q % withQ₄+Q₅+Q₆+Q₇+Q₈+Q % with Q₁+Q₂+Q₃+Q₄+Q₅+Q₆+Q₇, with Q₁+Q₂+Q₃+Q₄+Q₅+Q₆+Q₈,with Q₁+Q₂+Q₃+Q₄+Q₈+Q₆+Q₉, with Q₁+Q₃+Q₄+Q₅+Q₆+Q₇+Q₈, withQ₁+Q₃+Q₄+Q₅+Q₆+Q₇+Q₉, with Q₁+Q₄+Q₅+Q₆+Q₇+Q₈+Q₉, withQ₂+Q₃+Q₄+Q₅+Q₆+Q₇+Q₈, with Q₂+Q₃+Q₄+Q₈+Q₆+Q₇+Q₉, withQ₂+Q₃+Q₄+Q₅+Q₆+Q₈+Q₉, with Q₂+Q₄+Q₅+Q₆+Q₇+Q₈+Q₉, withQ₃+Q₄+Q₅+Q₆+Q₇+Q₈+Q₉, with Q₁+Q₂+Q₃+Q₄+Q₅+Q₆+Q₇+Q₈, withQ₁+Q₂+Q₃+Q₄+Q₅+Q₆+Q₇+Q₉, with Q₂+Q₃+Q₄+Q₅+Q₆+Q₇+Q₈+Q₉, or withQ₁+Q₂+Q₃+Q₄+Q₅+Q₆+Q₇+Q₈+Q₉.

Such combinations can be referred to as U4+Q₁, U4+Q₂, U4+Q₃, U4+Q₄,U4+Q₅, U4+Q₆, U4+Q₇, U4+Q₈, U4+Q₉, U4+Q₁+Q₂, U4+Q₁+Q₃, U4+Q₁+Q₄,U4+Q₁+Q₅, U4+Q₁+Q₆, U4+Q₁+Q₇, U4+Q₁+Q₈, U4+Q₁+Q₉, U4+Q₂+Q₃, U4+Q₂+Q₄,U4+Q₂+Q₅, U4+Q₂+Q₆, U4+Q₂+Q₇, U4+Q₂+Q₈, U4+Q₂+Q₉, U4+Q₃+Q₄, U4+Q₃+Q₅,U4+Q₃+Q₆, U4+Q₃+Q₇, U4+Q₃+Q₈, U4+Q₃+Q₉, U4+Q₄+Q₅, U4+Q₄+Q₆, U4+Q₄+Q₇,U4+Q₄+Q₈, U4+Q₄+Q₉, U4+Q₅+Q₆, U4+Q₅+Q₇, U4+Q₅+Q₈, U4+Q₅+Q₉, U4+Q₆+Q₇,U4+Q₆+Q₈, U4+Q₆+Q₉, U4+Q₇+Q₈, U4+Q₇+Q₉, U4+Q₈+Q₉, U4+Q₄+Q₂+Q₃,U4+Q₄+Q₂+Q₄, U4+Q₁+Q₂+Q₅, U4+Q₁+Q₂+Q₆, U4+Q₄+Q₂+Q₇, U4+Q₄+Q₂+Q₈,U4+Q₁+Q₂+Q₉, U4+Q₁+Q₃+Q₄, U4+Q₁+Q₃+Q₅, U4+Q₄+Q₃+Q₆, U4+Q₄+Q₃+Q₇,U4+Q₁+Q₃+Q₈, U4+Q₁+Q₃+Q₉, U4+Q₄+Q₄+Q₅, U4+Q₄+Q₄+Q₆, U4+Q₁+Q₄+Q₇,U4+Q₁+Q₄+Q₈, U4+Q₁+Q₄+Q₉, U4+Q₁+Q₅+Q₆, U4+Q₄+Q₅+Q₇, U4+Q₁+Q₅+Q₈,U4+Q₁+Q₅+Q₉, U4+Q₁+Q₆+Q₇, U4+Q₁+Q₆+Q₈, U4+Q₁+Q₆+Q₉, U4+Q₁+Q₇+Q₈,U4+Q₁+Q₇+Q₉, U4+Q₁+Q₈+Q₉, U4+Q₂+Q₃+Q₄, U4+Q₂+Q₃+Q₅, U4+Q₂+Q₃+Q₆,U4+Q₂+Q₃+Q₇, U4+Q₂+Q₃+Q₈, U4+Q₂+Q₃+Q₉, U4+Q₂+Q₄+Q₅, U4+Q₂+Q₄+Q₆,U4+Q₂+Q₄+Q₇, U4+Q₂+Q₄+Q₈, U4+Q₂+Q₄+Q₉, U4+Q₂+Q₅+Q₆, U4+Q₂+Q₅+Q₇,U4+Q₂+Q₅+Q₈, U4+Q₂+Q₅+Q₉, U4+Q₂+Q₆+Q₇, U4+Q₂+Q₆+Q₈, U4+Q₂+Q₆+Q₉,U4+Q₂+Q₇+Q₈, U4+Q₂+Q₇+Q₉, U4+Q₂+Q₈+Q₉, U4+Q₃+Q₄+Q₅, U4+Q₃+Q₄+Q₆,U4+Q₃+Q₄+Q₇, U4+Q₃+Q₄+Q₈, U4+Q₃+Q₄+Q₉, U4+Q₃+Q₅+Q₆, U4+Q₃+Q₅+Q₇,U4+Q₃+Q₅+Q₈, U4+Q₃+Q₅+Q₉, U4+Q₃+Q₆+Q₇, U4+Q₃+Q₆+Q₈, U4+Q₃+Q₆+Q₉,U4+Q₃+Q₇+Q₈, U4+Q₃+Q₇+Q₉, U4+Q₃+Q₈+Q₉, U4+Q₄+Q₅+Q₆, U4+Q₄+Q₅+Q₇,U4+Q₄+Q₅+Q₈, U4+Q₄+Q₅+Q₉, U4+Q₄+Q₆+Q₇, U4+Q₄+Q₆+Q₈, U4+Q₄+Q₆+Q₉,U4+Q₄+Q₇+Q₈, U4+Q₄+Q₇+Q₉, U4+Q₄+Q₈+Q₉, U4+Q₅+Q₆+Q₇, U4+Q₅+Q₆+Q₈,U4+Q₅+Q₆+Q₉, U4+Q₅+Q₇+Q₈, U4+Q₅+Q₇+Q₉, U4+Q₅+Q₈+Q₉, U4+Q₆+Q₇+Q₈,U4+Q₆+Q₇+Q₉, U4+Q₆+Q₈+Q₉, U4+Q₁+Q₂+Q₃+Q₄, U4+Q₁+Q₂+Q₃+Q₅,U4+Q₁+Q₂+Q₃+Q₆, U4+Q₁+Q₂+Q₃+Q₇, U4+Q₁+Q₂+Q₃+Q₈, U4+Q₁+Q₂+Q₃+Q₉,U4+Q₁+Q₃+Q₄+Q₅, U4+Q₁+Q₃+Q₄+Q₆, U4+Q₁+Q₃+Q₄+Q₇, U4+Q₁+Q₃+Q₄+Q₈,U4+Q₁+Q₃+Q₄+Q₉, U4+Q₁+Q₄+Q₅+Q₆, U4+Q₁+Q₄+Q₅+Q₇, U4+Q₁+Q₄+Q₅+Q₈,U4+Q₁+Q₄+Q₅+Q₉, U4+Q₁+Q₅+Q₆+Q₇, U4+Q₁+Q₅+Q₆+Q₈, U4+Q₁+Q₅+Q₆+Q₉,U4+Q₁+Q₆+Q₇+Q₈, U4+Q₁+Q₆+Q₇+Q₉, U4+Q₁+Q₇+Q₈+Q₉, U4+Q₂+Q₃+Q₄+Q₅,U4+Q₂+Q₃+Q₄+Q₆, U4+Q₂+Q₃+Q₄+Q₇, U4+Q₂+Q₃+Q₄+Q₈, U4+Q₂+Q₃+Q₄+Q₉,U4+Q₂+Q₄+Q₅+Q₆, U4+Q₂+Q₄+Q₅+Q₇, U4+Q₂+Q₄+Q₅+Q₈, U4+Q₂+Q₄+Q₅+Q₉,U4+Q₂+Q₅+Q₆+Q₇, U4+Q₂+Q₅+Q₆+Q₈, U4+Q₂+Q₅+Q₆+Q₉, U4+Q₂+Q₆+Q₇+Q₈,U4+Q₂+Q₆+Q₇+Q₉, U4+Q₂+Q₇+Q₈+Q₉, U4+Q₃+Q₄+Q₅+Q₆, U4+Q₃+Q₄+Q₅+Q₇,U4+Q₃+Q₄+Q₅+Q₈, U4+Q₃+Q₄+Q₅+Q₉, U4+Q₃+Q₅+Q₆+Q₇, U4+Q₃+Q₅+Q₆+Q₈,U4+Q₃+Q₅+Q₆+Q₉, U4+Q₃+Q₆+Q₇+Q₈, U4+Q₃+Q₆+Q₇+Q₉, U4+Q₃+Q₇+Q₈+Q₉,U4+Q₄+Q₅+Q₆+Q₇, U4+Q₄+Q₈+Q₆+Q₈, U4+Q₄+Q₅+Q₆+Q₉, U4+Q₄+Q₆+Q₇+Q₈,U4+Q₄+Q₆+Q₇+Q₉, U4+Q₄+Q₇+Q₈+Q₉, U4+Q₅+Q₆+Q₇+Q₈, U4+Q₅+Q₆+Q₇+Q₉,U4+Q₅+Q₇+Q₈+Q₉, U4+Q₁+Q₂+Q₃+Q₄+Q₅, U4+Q₁+Q₂+Q₃+Q₄+Q₆, U4+Q₄+Q₂+Q₃+Q₄+Q₇,U4+Q₁+Q₂+Q₃+Q₄+Q₈, U4+Q₁+Q₂+Q₃+Q₄+Q₉, U4+Q₁+Q₃+Q₄+Q₅+Q₆,U4+Q₁+Q₃+Q₄+Q₅+Q₇, U4+Q₄+Q₃+Q₄+Q₅+Q₈, U4+Q₁+Q₃+Q₄+Q₅+Q₉,U4+Q₁+Q₄+Q₅+Q₆+Q₇, U4+Q₁+Q₄+Q₅+Q₆+Q₈, U4+Q₁+Q₄+Q₅+Q₆+Q₉,U4+Q₁+Q₅+Q₆+Q₇+Q₈, U4+Q₁+Q₅+Q₆+Q₇+Q₉, U4+Q₁+Q₆+Q₇+Q₈+Q₉,U4+Q₂+Q₃+Q₄+Q₅+Q₆, U4+Q₂+Q₃+Q₄+Q₅+Q₇, U4+Q₂+Q₃+Q₄+Q₅+Q₈,U4+Q₂+Q₃+Q₄+Q₅+Q₉, U4+Q₂+Q₄+Q₅+Q₆+Q₇, U4+Q₂+Q₄+Q₅+Q₆+Q₈,U4+Q₂+Q₄+Q₅+Q₆+Q₉, U4+Q₂+Q₅+Q₆+Q₇+Q₈, U4+Q₂+Q₅+Q₆+Q₇+Q₉,U4+Q₂+Q₆+Q₇+Q₈+Q₉, U4+Q₃+Q₄+Q₅+Q₆+Q₇, U4+Q₃+Q₄+Q₅+Q₆+Q₈,U4+Q₃+Q₄+Q₅+Q₆+Q₉, U4+Q₃+Q₈+Q₆+Q₇+Q₈, U4+Q₃+Q₅+Q₆+Q₇+Q₉,U4+Q₃+Q₆+Q₇+Q₈+Q₉, U4+Q₄+Q₅+Q₆+Q₇+Q₈, U4+Q₄+Q₅+Q₆+Q₇+Q₉,U4+Q₄+Q₆+Q₇+Q₈+Q₉, U4+Q₅+Q₆+Q₇+Q₈+Q₉, U4+Q₁+Q₂+Q₃+Q₄+Q₅+Q₆,U4+Q₁+Q₂+Q₃+Q₄+Q₈+Q₇, U4+Q₁+Q₂+Q₃+Q₄+Q₅+Q₈, U4+Q₁+Q₂+Q₃+Q₄+Q₅+Q₉,U4+Q₁+Q₃+Q₄+Q₅+Q₆+Q₇, U4+Q₁+Q₃+Q₄+Q₅+Q₆+Q₈, U4+Q₁+Q₃+Q₄+Q₈+Q₆+Q₉,U4+Q₁+Q₄+Q₅+Q₆+Q₇+Q₈, U4+Q₁+Q₄+Q₅+Q₆+Q₇+Q₉, U4+Q₁+Q₅+Q₆+Q₇+Q₈+Q₉,U4+Q₂+Q₃+Q₄+Q₅+Q₆+Q₇, U4+Q₂+Q₃+Q₄+Q₅+Q₆+Q₈, U4+Q₂+Q₃+Q₄+Q₅+Q₆+Q₉,U4+Q₂+Q₄+Q₅+Q₆+Q₇+Q₈, U4+Q₂+Q₄+Q₅+Q₆+Q₇+Q₉, U4+Q₂+Q₅+Q₆+Q₇+Q₈+Q₉,U4+Q₃+Q₄+Q₅+Q₆+Q₇+Q₈, U4+Q₃+Q₄+Q₅+Q₆+Q₇+Q₉, U4+Q₃+Q₅+Q₆+Q₇+Q₈+Q₉,U4+Q₄+Q₅+Q₆+Q₇+Q₈+Q₉, U4+Q₁+Q₂+Q₃+Q₄+Q₅+Q₆+Q₇, U4+Q₁+Q₂+Q₃+Q₄+Q₅+Q₆+Q₈,U4+Q₁+Q₂+Q₃+Q₄+Q₅+Q₆+Q₉, U4+Q₁+Q₃+Q₄+Q₅+Q₆+Q₇+Q₈,U4+Q₁+Q₃+Q₄+Q₅+Q₆+Q₇+Q₉, U4+Q₁+Q₄+Q₅+Q₆+Q₇+Q₈+Q₉,U4+Q₂+Q₃+Q₄+Q₅+Q₆+Q₇+Q₈, U4+Q₂+Q₃+Q₄+Q₅+Q₆+Q₇+Q₉,U4+Q₂+Q₃+Q₄+Q₅+Q₆+Q₈+Q₉, U4+Q₂+Q₄+Q₈+Q₆+Q₇+Q₈+Q₉,U4+Q₃+Q₄+Q₅+Q₆+Q₇+Q₈+Q₉, U4+Q₁+Q₂+Q₃+Q₄+Q₈+Q₆+Q₇+Q₈,U4+Q₁+Q₂+Q₃+Q₄+Q₅+Q₆+Q₇+Q₉, U4+Q₂+Q₃+Q₄+Q₈+Q₆+Q₇+Q₈+Q₉, andU4+Q₁+Q₂+Q₃+Q₄+Q₅+Q₆+Q₇+Q₈+Q₉, respectively.

As used herein, J₁ represents the groups substituted or unsubstitutedC₁-C₁₀ alkyl, C₁-C₁₀ alkylene, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₁₀alkoxy, C₁-C₁₀ alkylamino, C₁-C₁₀ alkylthio, C₁-C₁₀ carbonyl, C₁-C₁₀carboxyl, C₁-C₁₀ amido, C₁-C₁₀ sulfonyl, C₁-C₁₀ sulfonic acid, C₁-C₁₀sulfamoyl, C₁-C₁₀ sulfoxide, C₁-C₁₀ phosphoryl, C₁-C₁₀ phosphonyl, C₁-C₉alkyl, C₁-C₉ alkylene, C₂-C₉ alkenyl, C₂-C₉ alkynyl, C₁-C₉ alkoxy, C₁-C₉alkylamino, C₁-C₉ alkylthio, C₁-C₉ carbonyl, C₁-C₉ carboxyl, C₁-C₉amido, C₁-C₉ sulfonyl, C₁-C₉ sulfonic acid, C₁-C₉ sulfamoyl, C₁-C₉sulfoxide, C₁-C₉ phosphoryl, C₁-C₉ phosphonyl, C₁-C₈ alkyl, C₁-C₈alkylene, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₁-C₈ alkoxy, C₁-C₈ alkylamino,C₁-C₈ alkylthio, C₁-C₈ carbonyl, C₁-C₈ carboxyl, C₁-C₈ amido, C₁-C₈sulfonyl, C₁-C₈ sulfonic acid, C₁-C₈ sulfamoyl, C₁-C₈ sulfoxide, C₁-C₈phosphoryl, C₁-C₈ phosphonyl, C₁-C₇ alkyl, C₁-C₇ alkylene, C₂-C₇alkenyl, C₂-C₇ alkynyl, C₁-C₇ alkoxy, C₁-C₇ alkylamino, C₁-C₇ alkylthio,C₁-C₇ carbonyl, C₁-C₇ carboxyl, C₁-C₇ amino, C₁-C₇ amido, C₁-C₇sulfonyl, C₁-C₇ sulfonic acid, C₁-C₇ sulfamoyl, C₁-C₇ sulfoxide, C₁-C₇phosphoryl, C₁-C₇ phosphonyl, C₁-C₆ alkyl, C₁-C₆ alkylene, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆ alkylthio,C₁-C₆ carbonyl, C₁-C₆ carboxyl, C₁-C₆ amido, C₁-C₆ sulfonyl, C₁-C₆sulfonic acid, C₁-C₆ sulfamoyl, C₁-C₆ sulfoxide, C₂-C₆ phosphoryl, C₂-C₆phosphonyl, C₁-C₅ alkyl, C₁-C₅ alkylene, C₂-C₅ alkenyl, C₂-C₅ alkynyl,C₁-C₅ alkoxy, C₁-C₅ alkylamino, C₁-C₅ alkylthio, C₁-C₅ carbonyl, C₁-C₅carboxyl, C₁-C₅ amido, C₁-C₅ sulfonyl, C₁-C₅ sulfonic acid, C₁-C₅sulfamoyl, C₁-C₅ sulfoxide, C₁-C₅ phosphoryl, C₁-C₅ phosphonyl, C₁-C₄alkyl, C₁-C₄ alkylene, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, C₁-C₄alkylamino, C₁-C₄ alkylthio, C₁-C₄ carbonyl, C₁-C₄ carboxyl, C₁-C₄amino, C₁-C₄ amido, C₁-C₄ sulfonyl, C₁-C₄ sulfonic acid, C₁-C₄sulfamoyl, C₁-C₄ sulfoxide, C₁-C₄ phosphoryl, C₁-C₄ phosphonyl, C₁-C₃alkyl, C₁-C₃ alkylene, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, C₁-C₃alkylamino, C₁-C₃ alkylthio, C₁-C₃ carbonyl, C₁-C₃ carboxyl, C₁-C₃amino, C₁-C₃ amido, C₁-C₃ sulfonyl, C₁-C₃ sulfonic acid, C₁-C₃sulfamoyl, C₁-C₃ sulfoxide, C₁-C₃ phosphoryl, C₁-C₃ phosphonyl, C₁-C₂alkyl, C₁-C₂ alkylene, C₁-C₂ alkoxy, C₁-C₂ alkylamino, C₁-C₂ alkylthio,C₁-C₂ carbonyl, C₁-C₂ carboxyl, C₁-C₂ amido, C₁-C₂ sulfonyl, C₁-C₂sulfonic acid, C₁-C₂ sulfamoyl, C₁-C₂ sulfoxide, C₁-C₂ phosphoryl, C₁-C₂phosphonyl, C₀-C₁₀ sulfonyl, C₀-C₁₀ sulfonic acid, C₀-C₁₀ sulfamoyl,C₀-C₁₀ sulfoxide, C₀-C₁₀ phosphoryl, C₀-C₁₀ phosphonyl, C₀-C₉ sulfonyl,C₀-C₉ sulfonic acid, C₀-C₉ sulfamoyl, C₀-C₉ sulfoxide, C₀-C₉ phosphoryl,C₀-C₉ phosphonyl, C₀-C₈ sulfonyl, C₀-C₈ sulfonic acid, C₀-C₈ sulfamoyl,C₀-C₈ sulfoxide, C₀-C₈ phosphoryl, C₀-C₈ phosphonyl, C₀-C₇ sulfonyl,C₀-C₇ sulfonic acid, C₀-C₇ sulfamoyl, C₀-C₇ sulfoxide, C₀-C₇ phosphoryl,C₀-C₇ phosphonyl, C₀-C₆ sulfonyl, C₀-C₆ sulfonic acid, C₀-C₆ sulfamoyl,C₀-C₆ sulfoxide, C₀-C₆ phosphoryl, C₀-C₆ phosphonyl, C₀-C₅ sulfonyl,C₀-C₅ sulfonic acid, C₀-C₅ sulfamoyl, C₀-C₅ sulfoxide, C₀-C₅ phosphoryl,C₀-C₅ phosphonyl, C₀-C₄ sulfonyl, C₀-C₄ sulfonic acid, C₀-C₄ sulfamoyl,C₀-C₄ sulfoxide, C₀-C₄ phosphoryl, C₀-C₄ phosphonyl, C₀-C₃ sulfonyl,C₀-C₃ sulfonic acid, C₀-C₃ sulfamoyl, C₀-C₃ sulfoxide, C₀-C₃ phosphoryl,C₀-C₃ phosphonyl, C₀-C₂ sulfonyl, C₀-C₂ sulfonic acid, C₀-C₂ sulfamoyl,C₀-C₂ sulfoxide, C₀-C₂ phosphoryl, C₀-C₂ phosphonyl, C₀-C1 sulfonyl,C₀-C1 sulfonic acid, C₀-C1 sulfamoyl, C₀-C1 sulfoxide, C₀-C1 phosphoryl,C₀-C1 phosphonyl, C₁₀ alkyl, C₁₀ alkylene, C₁₀ alkenyl, C₁₀ alkynyl, C₁₀alkoxy, C₁₀ alkylamino, C₁₀ alkylthio, C₁₀ carbonyl, C₁₀ carboxyl, C₁₀amido, C₁₀ sulfonyl, C₁₀ sulfonic acid, C₁₀ sulfamoyl, C₁₀ sulfoxide,C₁₀ phosphoryl, C₁₀ phosphonyl, C₉ alkyl, C₉ alkylene, C₉ alkenyl, C₉alkynyl, C₉ alkoxy, C₉ alkylamino, C₉ alkylthio, C₉ carbonyl, C₉carboxyl, C₉ amido, C₉ sulfonyl, C₉ sulfonic acid, C₉ sulfamoyl, C₉sulfoxide, C₉ phosphoryl, C₉ phosphonyl, C₈ alkyl, C₈ alkylene, C₈alkenyl, C₈ alkynyl, C₈ alkoxy, C₈ alkylamino, C₈ alkylthio, C₈carbonyl, C₈ carboxyl, C₈ amido, C₈ sulfonyl, C₈ sulfonic acid, C₈sulfamoyl, C₈ sulfoxide, C₈ phosphoryl, C₈ phosphonyl, C₇ alkyl, C₇alkylene, C₇ alkenyl, C₇ alkynyl, C₇ alkoxy, C₇ alkylamino, C₇alkylthio, C₇ carbonyl, C₇ carboxyl, C₇ amido, C₇ sulfonyl, C₇ sulfonicacid, C₇ sulfamoyl, C₇ sulfoxide, C₇ phosphoryl, C₇ phosphonyl, C₆alkyl, C₆ alkylene, C₆ alkenyl, C₆ alkynyl, C₆ alkoxy, C₆ alkylamino, C₆alkylthio, C₆ carbonyl, C₆ carboxyl, C₆ amido, C₆ sulfonyl, C₆ sulfonicacid, C₆ sulfamoyl, C₆ sulfoxide, C₆ phosphoryl, C₆ phosphonyl, C₅alkyl, C₅ alkylene, C₅ alkenyl, C₅ alkynyl, C₅ alkoxy, C₅ alkylamino, C₅alkylthio, C₅ carbonyl, C₅ carboxyl, C₅ amido, C₅ sulfonyl, C₅ sulfonicacid, C₅ sulfamoyl, C₅ sulfoxide, C₅ phosphoryl, C₅ phosphonyl, C₄alkyl, C₄ alkylene, C₄ alkenyl, C₄ alkynyl, C₄ alkoxy, C₄ alkylamino, C₄alkylthio, C₄ carbonyl, C₄ carboxyl, C₄ amido, C₄ sulfonyl, C₄ sulfonicacid, C₄ sulfamoyl, C₄ sulfoxide, C₄ phosphoryl, C₄ phosphonyl, C₃alkyl, C₃ alkylene, C₃ alkenyl, C₃ alkynyl, C₃ alkoxy, C₃ alkylamino, C₃alkylthio, C₃ carbonyl, C₃ carboxyl, C₃ amido, C₃ sulfonyl, C₃ sulfonicacid, C₃ sulfamoyl, C₃ sulfoxide, C₃ phosphoryl, C₃ phosphonyl, C₂alkyl, C₂ alkylene, C₂ alkenyl, C₂ alkynyl, C₂ alkoxy, C₂ alkylamino, C₂alkylthio, C₂ carbonyl, C₂ carboxyl, C₂ amido, C₂ sulfonyl, C₂ sulfonicacid, C₂ sulfamoyl, C₂ sulfoxide, C₂ phosphoryl, C₂ phosphonyl, C₁alkyl, C₁ alkylene, C₁ alkoxy, C₁ alkylamino, C₁ alkylthio, C₁ carbonyl,C₁ carboxyl, C₁ amido, C₁ sulfonyl, C₁ sulfonic acid, C₁ sulfamoyl, C₁sulfoxide, C₁ phosphoryl, C₁ phosphonyl, C₀ sulfonyl, C₀ sulfonic acid,C₀ sulfamoyl, C₀ sulfoxide, C₀ phosphoryl, and C₀ phosphonyl.

As used herein, J₂ represents the organic groups substituted orunsubstituted C₁-C₁₀ alkyl, C₁-C₁₀ alkylene, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₁-C₁₀ alkoxy, C₁-C₁₀ alkylamino, C₁-C₁₀ alkylthio, C₄-C₉alkyl, C₁-C₉ alkylene, C₂-C₉ alkenyl, C₂-C₉ alkynyl, C₁-C₉ alkoxy, C₁-C₉alkylamino, C₁-C₉ alkylthio, C₁-C₈ alkyl, C₁-C₈ alkylene, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₁-C₈ alkoxy, C₁-C₈ alkylamino, C₁-C₈ alkylthio, C₁-C₇alkyl, C₁-C₇ alkylene, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₁-C₇ alkoxy, C₁-C₇alkylamino, C₁-C₇ alkylthio, C₁-C₆ alkyl, C₁-C₆ alkylene, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₁-C₆ alkoxy, Cr C₆ alkylamino, C₁-C₆ alkylthio, C₁-C₅alkyl, C₁-C₅ alkylene, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₁-C₅ alkoxy, C₁-C₅alkylamino, C₁-C₅ alkylthio, C₁-C₄ alkyl, C₁-C₄ alkylene, C₂-C₄ alkenyl,C₂-C₄ alkynyl, C₁-C₄ alkoxy, C₁-C₄ alkylamino, C₁-C₄ alkylthio, C₁-C₃alkyl, C₁-C₃ alkylene, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, C₁-C₃alkylamino, Cr C₃ alkylthio, C₁-C₂ alkyl, C₁-C₂ alkylene, C₁-C₂ alkoxy,C₁-C₂ alkylamino, C₁-C₂ alkylthio, C₁₀ alkyl, C₁₀ alkylene, C₁₀ alkenyl,C₁₀ alkynyl, C₁₀ alkoxy, C₁₀ alkylamino, C₁₀ alkylthio, C₉ alkyl, C₉alkylene, C₉ alkenyl, C₉ alkynyl, C₉ alkoxy, C₉ alkylamino, C₉alkylthio, C₈ alkyl, C₈ alkylene, C₈ alkenyl, C₈ alkynyl, C₈ alkoxy, C₈alkylamino, C₈ alkylthio, C₇ alkyl, C₇ alkylene, C₇ alkenyl, C₇ alkynyl,C₇ alkoxy, C₇ alkylamino, C₇ alkylthio, C₆ alkyl, C₆ alkylene, C₆alkenyl, C₆ alkynyl, C₆ alkoxy, C₆ alkylamino, C₆ alkylthio, C₅ alkyl,C₅ alkylene, C₅ alkenyl, C₅ alkynyl, C₅ alkoxy, C₅ alkylamino, C₅alkylthio, C₄ alkyl, C₄ alkylene, C₄ alkenyl, C₄ alkynyl, C₄ alkoxy, C₄alkylamino, C₄ alkylthio, C₃ alkyl, C₃ alkylene, C₃ alkenyl, C₃ alkynyl,C₃ alkoxy, C₃ alkylamino, C₃ alkylthio, C₂ alkyl, C₂ alkylene, C₂alkenyl, C₂ alkynyl, C₂ alkoxy, C₂ alkylamino, C₂ alkylthio, C₄ alkyl,C₁ alkylene, C₁ alkoxy, C₁ alkylamino, and C₁ alkylthio.

II. Modified Alginates

Described herein are alginate polymers that have been chemicallymodified to alter their biocompatibility and physical properties, aswell as methods of making thereof.

A. Structure of Modified Alginate Polymers

Modified alginates contain one or more covalently modified monomersdefined by Formula I

In some embodiments, the modified alginate is defined by Formula Ia,Formula Ib, or a combination of Formula Ia and Formula Ib

wherein, for Formula I, Formula Ia or Formula Ib,

X is oxygen, sulfur, or NR₄;

R₁ is hydrogen, or an organic grouping containing any number of carbonatoms, preferably 1-30 carbon atoms, more preferably 1-20 carbon atoms,more preferably 1-14 carbon atoms, and optionally including one or moreheteroatoms such as oxygen, sulfur, or nitrogen grouping in linear,branched, or cyclic structural formats, representative R₁ groupingsbeing those present in U₁, U₁+Q₁; Q₁+Q₂, Q₁+Q₃, Q₁+Q₄, Q₁+Q₁+Q₂,U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃,U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferablyU₁+Q₁+Q₂+Q₃;

Y₁ and Y₂ independently are hydrogen or —PO(OR₅)₂; or

Y₂ is absent, and Y_(2J) together with the two oxygen atoms to which Y₁and Y₂ are attached form a cyclic structure as shown in Formula II,Formula IIa, Formula IIb, or a combination of Formula IIa and FormulaIIb

wherein for Formula II, Formula IIa or Formula IIb,

R₂ and R₃ are, independently, hydrogen or an organic grouping containingany number of carbon atoms, preferably 1-30 carbon atoms, morepreferably 1-20 carbon atoms, more preferably 1-14 carbon atoms, andoptionally including one or more heteroatoms such as oxygen, sulfur, ornitrogen grouping in linear, branched, or cyclic structural formats,representative R₂ and R₃ groupings being those present in U. U₁+Q₁;U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₄+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃; or

R₂ and R₃, together with the carbon atom to which they are attached,form a 3- to 8-membered unsubstituted or substituted carbocyclic orheterocyclic ring; and

R₄ and R₅ are, independently, hydrogen or an organic grouping containingany number of carbon atoms, preferably 1-30 carbon atoms, morepreferably 1-20 carbon atoms, more preferably 1-14 carbon atoms, andoptionally including one or more heteroatoms such as oxygen, sulfur, ornitrogen grouping in linear, branched, or cyclic structural formats,representative R₄ and R₅ groupings being those present in U. U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

In some embodiments, R₁ is, independently in one or more sites ofchemical modification,

-A-B(—C)_(δ),   Formula XVI

wherein

A is hydrogen or an organic grouping containing any number of carbonatoms, 1-carbon atoms, 1-20 carbon atoms, or 1-14 carbon atoms, andoptionally including one or more heteroatoms such as oxygen, sulfur, ornitrogen grouping in linear, branched, or cyclic structural formats,representative organic groupings being those present in U₁; U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU_(x)+Q_(x)+Q₂+Q₃+Q₄, preferably U_(x)+Q_(x)+Q₃;

B, and C are, independently, absent, hydrogen, or an organic groupingcontaining any number of carbon atoms, 1-30 carbon atoms, 1-20 carbonatoms, or 1-14 carbon atoms, and optionally including one or moreheteroatoms such as oxygen, sulfur, or nitrogen grouping in linear,branched, or cyclic structural formats, representative organic groupingsbeing those present in U₁; U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂,U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃,U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferablyU₁+Q₁+Q₃; and

δ is an integer from, as valency permits, 0 to 30.

In some embodiments, R is, independently in one or more sites ofchemical modification,

—R₆—R^(b),   Formula XVIII

wherein

R₆ is hydrogen or an organic grouping containing any number of carbonatoms, 1-30 carbon atoms, 1-20 carbon atoms, or 1-14 carbon atoms, andoptionally including one or more heteroatoms such as oxygen, sulfur, ornitrogen grouping in linear, branched, or cyclic structural formats,representative Re organic groupings being those present in U₁; U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃; and

R^(b) is absent, hydrogen, or an organic grouping containing any numberof carbon atoms, 1-30 carbon atoms, 1-20 carbon atoms, or 1-14 carbonatoms, and optionally including one or more heteroatoms such as oxygen,sulfur, or nitrogen grouping in linear, branched, or cyclic structuralformats, representative R^(b) organic groupings being those present inU₁; U₁+Q₁; U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

In some embodiments of R₁; R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R^(a), R^(b),R^(c), R^(d), R^(e), A, B, C, -A-B(—C)₆, —B(—C)₆, —B, and independentlyin combination with any embodiments of any other relevant substituentclasses, R₁; R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R^(a), R^(b), R^(c), R^(d),R^(e), A, B, C, -A-B(—C)_(δ), —B(—C)_(δ), —B can be, independently,absent, hydrogen, or an organic grouping containing any number of carbonatoms, 1-30 carbon atoms, 1-20 carbon atoms, or 1-14 carbon atoms, andoptionally including one or more heteroatoms such as oxygen, sulfur, ornitrogen grouping in linear, branched, or cyclic structural formats,representative R. R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R^(a), R^(b), R^(c),R^(d), R^(e), A, B, C, -A-B(—C)₆, —B(—C)₆, —B organic groupings beingthose present in U₁+Q₁; U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₅, U₁+Q₁+Q₂, U₁+Q₁+Q₃,U₁+Q₁+Q₄, U₁+Q₁+Q₅, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₂+Q₅, U₁+Q₃+Q₄, U₁+Q₃+Q₅,U₁+Q₄+Q₅, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₂+Q₅, U₁+Q₁+Q₃+Q₄,U₁+Q₁+Q₃+Q₅, U₁+Q₁+Q₄+Q₅, U₁+Q₂+Q₃+Q₄, U₁+Q₂+Q₃+Q₅, U₁+Q₂+Q₄+Q₅,U₁+Q₃+Q₄+Q₅, U₁+Q₁+Q₂+Q₃+Q₄, U₁+Q₁+Q₂+Q₃+Q₅, U₁+Q₁+Q₂+Q₄+Q₅,U₁+Q₁+Q₃+Q₄+Q₅, U₁+Q₂+Q₃+Q₄+Q₅, or U₁+Q₁+Q₂+Q₃+Q₄, +Q₈.

In some embodiments of R₁; R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R^(a), R^(b),R^(c), R^(d), R^(e), A, B, C, -A-B(—C)₆, —B(—C)₆, —B, and independentlyin combination with any embodiments of any other relevant substituentclasses, R₁; R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R^(a), R^(b), R^(c), R^(d),R^(e), A, B, C, -A-B(—C)_(δ), —B(—C)_(δ), —B can be, independently,absent, hydrogen, or an organic grouping containing any number of carbonatoms, 1-30 carbon atoms, 1-20 carbon atoms, or 1-14 carbon atoms, andoptionally including one or more heteroatoms such as oxygen, sulfur, ornitrogen grouping in linear, branched, or cyclic structural formats,representative R. R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R^(a), R^(b), R^(c),R^(d), R^(e), A, B, C, -A-B(—C)₆, —B(—C)₆, —B organic groupings beingthose present in U4+Q₁; U4+Q₂, U4+Q₃, U4+Q₄, U4+Q₅, U4+Q₆, U4+Q₇, U4+Q₈,U4+Q₉, U4+Q₁+Q₂, U4+Q₁+Q₃, U4+Q₁+Q₄, U4+Q₁+Q₅, U4+Q₁+Q₆, U4+Q₁+Q₇,U4+Q₁+Q₈, U4+Q₁+Q₉, U4+Q₂+Q₃, U4+Q₂+Q₄, U4+Q₂+Q₅, U4+Q₂+Q₆, U4+Q₂+Q₇,U4+Q₂+Q₈, U4+Q₂+Q₉, U4+Q₃+Q₄, U4+Q₃+Q₅, U4+Q₃+Q₆, U4+Q₃+Q₇, U4+Q₃+Q₈,U4+Q₃+Q₉, U4+Q₄+Q₅, U4+Q₄+Q₆, U4+Q₄+Q₇, U4+Q₄+Q₈, U4+Q₄+Q₉, U4+Q₅+Q₆,U4+Q₅+Q₇, U4+Q₅+Q₈, U4+Q₅+Q₉, U4+Q₆+Q₇, U4+Q₆+Q₈, U4+Q₆+Q₉, U4+Q₇+Q₈,U4+Q₇+Q₉, U4+Q₈+Q₉, U4+Q₄+Q₂+Q₃, U4+Q₁+Q₂+Q₄, U4+Q₁+Q₂+Q₅, U4+Q₄+Q₂+Q₆,U4+Q₄+Q₂+Q₇, U4+Q₁+Q₂+Q₈, U4+Q₁+Q₂+Q₉, U4+Q₄+Q₃+Q₄, U4+Q₄+Q₃+Q₅,U4+Q₄+Q₃+Q₆, U4+Q₁+Q₃+Q₇, U4+Q₁+Q₃+Q₈, U4+Q₄+Q₃+Q₉, U4+Q₄+Q₄+Q₅,U4+Q₁+Q₄+Q₆, U4+Q₁+Q₄+Q₇, U4+Q₄+Q₄+Q₈, U4+Q₄+Q₄+Q₉, U4+Q₁+Q₅+Q₆,U4+Q₁+Q₅+Q₇, U4+Q₁+Q₅+Q₈, U4+Q₁+Q₅+Q₉, U4+Q₁+Q₆+Q₇, U4+Q₁+Q₆+Q₈,U4+Q₁+Q₆+Q₉, U4+Q₁+Q₇+Q₈, U4+Q₁+Q₇+Q₉, U4+Q₁+Q₈+Q₉, U4+Q₂+Q₃+Q₄,U4+Q₂+Q₃+Q₅, U4+Q₂+Q₃+Q₆, U4+Q₂+Q₃+Q₇, U4+Q₂+Q₃+Q₈, U4+Q₂+Q₃+Q₉,U4+Q₂+Q₄+Q₅, U4+Q₂+Q₄+Q₆, U4+Q₂+Q₄+Q₇, U4+Q₂+Q₄+Q₈, U4+Q₂+Q₄+Q₉,U4+Q₂+Q₅+Q₆, U4+Q₂+Q₅+Q₇, U4+Q₂+Q₅+Q₈, U4+Q₂+Q₅+Q₉, U4+Q₂+Q₆+Q₇,U4+Q₂+Q₆+Q₈, U4+Q₂+Q₆+Q₉, U4+Q₂+Q₇+Q₈, U4+Q₂+Q₇+Q₉, U4+Q₂+Q₈+Q₉,U4+Q₃+Q₄+Q₅, U4+Q₃+Q₄+Q₉, U4+Q₃+Q₄+Q₇, U4+Q₃+Q₄+Q₈, U4+Q₃+Q₄+Q₉,U4+Q₃+Q₅+Q₆, U4+Q₃+Q₅+Q₇, U4+Q₃+Q₅+Q₈, U4+Q₃+Q₅+Q₉, U4+Q₃+Q₆+Q₇,U4+Q₃+Q₆+Q₈, U4+Q₃+Q₆+Q₉, U4+Q₃+Q₇+Q₈, U4+Q₃+Q₇+Q₉, U4+Q₃+Q₈+Q₉,U4+Q₄+Q₅+Q₆, U4+Q₄+Q₅+Q₇, U4+Q₄+Q₅+Q₈, U4+Q₄+Q₅+Q₉, U4+Q₄+Q₆+Q₇,U4+Q₄+Q₆+Q₈, U4+Q₄+Q₆+Q₉, U4+Q₄+Q₇+Q₈, U4+Q₄+Q₇+Q₉, U4+Q₄+Q₈+Q₉,U4+Q₅+Q₆+Q₇, U4+Q₅+Q₆+Q₈, U4+Q₅+Q₆+Q₉, U4+Q₅+Q₇+Q₈, U4+Q₅+Q₇+Q₉,U4+Q₅+Q₈+Q₉, U4+Q₆+Q₇+Q₈, U4+Q₆+Q₇+Q₉, U4+Q₆+Q₈+Q₉, U4+Q₁+Q₂+Q₃+Q₄,U4+Q₁+Q₂+Q₃+Q₅, U4+Q₁+Q₂+Q₃+Q₆, U4+Q₁+Q₂+Q₃+Q₇, U4+Q₁+Q₂+Q₃+Q₈,U4+Q₁+Q₂+Q₃+Q₉, U4+Q₁+Q₃+Q₄+Q₅, U4+Q₁+Q₃+Q₄+Q₆, U4+Q₁+Q₃+Q₄+Q₇,U4+Q₁+Q₃+Q₄+Q₈, U4+Q₁+Q₃+Q₄+Q₉, U4+Q₁+Q₄+Q₅+Q₆, U4+Q₁+Q₄+Q₅+Q₇,U4+Q₁+Q₄+Q₅+Q₈, U4+Q₁+Q₄+Q₅+Q₉, U4+Q₁+Q₅+Q₆+Q₇, U4+Q₁+Q₅+Q₆+Q₈,U4+Q₁+Q₅+Q₆+Q₉, U4+Q₁+Q₆+Q₇+Q₈, U4+Q₁+Q₆+Q₇+Q₉, U4+Q₁+Q₇+Q₈+Q₉,U4+Q₂+Q₃+Q₄+Q₅, U4+Q₂+Q₃+Q₄+Q₆, U4+Q₂+Q₃+Q₄+Q₇, U4+Q₂+Q₃+Q₄+Q₈,U4+Q₂+Q₃+Q₄+Q₉, U4+Q₂+Q₄+Q₈+Q₉, U4+Q₂+Q₄+Q₅+Q₇, U4+Q₂+Q₄+Q₅+Q₈,U4+Q₂+Q₄+Q₅+Q₉, U4+Q₂+Q₅+Q₆+Q₇, U4+Q₂+Q₅+Q₆+Q₈, U4+Q₂+Q₈+Q₆+Q₉,U4+Q₂+Q₆+Q₇+Q₈, U4+Q₂+Q₆+Q₇+Q₉, U4+Q₂+Q₇+Q₈+Q₉, U4+Q₃+Q₄+Q₅+Q₆,U4+Q₃+Q₄+Q₅+Q₇, U4+Q₃+Q₄+Q₅+Q₈, U4+Q₃+Q₄+Q₅+Q₉, U4+Q₃+Q₅+Q₆+Q₇,U4+Q₃+Q₅+Q₆+Q₈, U4+Q₃+Q₅+Q₆+Q₉, U4+Q₃+Q₆+Q₇+Q₈, U4+Q₃+Q₆+Q₇+Q₉,U4+Q₃+Q₇+Q₈+Q₉, U4+Q₄+Q₅+Q₆+Q₇, U4+Q₄+Q₅+Q₆+Q₈,U4+Q₄+Q₅+Q₆+Q₉,+U₄+Q₄+Q₆+Q₇+Q₈, U4+Q₄+Q₆+Q₇+Q₉,+U4+Q₄+Q₇+Q₈+Q₉,+U4+Q₅+Q₆+Q₇+Q₈, +U4+Q₅+Q₆+Q₇+Q₉,U4+Q₅+Q₇+Q₈+Q₉,+U4+Q₁+Q₂+Q₃+Q₄+Q₅,+U4+Q₁+Q₂+Q₃+Q₄+Q₆,+U4+Q₁+Q₂+Q₃+Q₄+Q₇+U4+Q₁+Q₂+Q₃+Q₄+Q₈,+U4+Q₁+Q₂+Q₃+Q₄+Q₉,+U4+Q₁+Q₃+Q₄+Q₅+Q₆+U4+Q₁+Q₃+Q₄+Q₅+Q₇+U4+Q₁+Q₃+Q₄+Q₅+Q₈+U4+Q₁+Q₃+Q₄+Q₅+Q₉,+U4+Q₁+Q₄+Q₅+Q₆+Q₇,U4+Q₁+Q₄+Q₅+Q₆+Q₈,+U4+Q₁Q₄+Q₅+Q₆+Q₉,U4+Q₁+Q₅+Q₆+Q₇+Q₈,+U4+Q₁+Q₅+Q₆+Q₇+Q₉,+U4+Q₁+Q₆+Q₇+Q₈+Q₉,U4+Q₂+Q₃+Q₄+Q₅+Q₆,+U4+Q₂+Q₃+Q₄+Q₅+Q₇,+U4+Q₂+Q₃+Q₄+Q₅+Q₈+U4+Q₂₊Q₃+Q₄+Q₅+Q₉,+U4+Q₂+Q₄+Q₅+Q₅+Q₇,+U4+Q₂+Q₄+Q₅+Q₆+Q₈,+U4+Q₂+Q₄+Q₅+Q₆+Q₉,U4+Q₂+Q₅+Q₆+Q₇+Q₈,+U4+Q₂+Q₅+Q₆+Q₇+Q₉,+U4+Q₂+Q₆+Q₇+Q₈+Q₉,+U4+Q₃+Q₄+Q₅+Q₆+Q₇,+U4+Q₃+Q₄₊Q₅+Q₆+Q₈,U4+Q₃+Q₄+Q₅+Q₆+Q₉,+U4+Q₃+Q₅+Q₆+Q₇+Q₈,+U4+Q₃+Q₅+Q₆+Q₇+Q₉, U4+Q₃+Q₆+Q₇+Q₈+Q₉,+U4+Q₄+Q₅+Q₆+Q₇+Q₈,+U4+Q₄+Q₅Q₆+Q₇+Q₉,U4+Q₄+Q₆₊Q₇+Q₈+Q₉,+U4+Q₅+Q₆+Q₇+Q₈+Q₉,+U4+Q₁+Q₂+Q₃+Q₄+Q₅+Q₆,+U4+Q₁+Q₂+Q₃,Q₄+Q₅+Q₇, U4+Q₁+Q₂+Q₃Q₄+Q₅+Q₈,+U4+Q₁+Q₂,+Q₃+Q₄+Q₅+Q₉,+U4+Q₁+Q₃+Q₄+Q₅+Q₆+Q₇,+U4+Q₁+Q₃+Q₄+Q₅+Q₆+Q₈U4+Q₁+Q₃+Q₄+Q₅+Q₆+Q₉,+U4+Q₁+Q₄+Q₅+Q₆+Q₇+Q₈,U4+Q₁+Q₄+Q₅+Q₆+Q₇+Q₉,+U4+Q₁+Q₅+Q₆+Q₇+Q₈+Q₉,+U4+Q₂+Q₃+Q₄+Q₅+Q₆+Q₇,+U4+Q₂+Q₃+Q₄+Q₅+Q₆+Q₈,+U4+Q₂+Q₃+Q₄+Q₅++Q₆+Q₉,+U4+Q₂+Q₄+Q₅+Q₆+Q₇+Q₈,+U4+Q₂+Q₄+Q₅+Q₆+Q₇+Q₉,+U4+Q₂Q₅+Q₆Q₇+Q₈Q₉,U4+Q₃+Q₄+Q₅+Q₆+Q₇+Q₈,+U4+Q₃+Q₄+Q₅+Q₆+Q₇+Q₉,+U4+Q₃+Q₅+Q₆+Q₇+Q₈+Q₉,+U4+Q₄+Q₅+Q₆+Q₇+Q₈+Q₉,+U4+Q₁₊Q₂+Q₃+Q₄+Q₅+Q₆+Q₇,+U4+Q₁+Q₂+Q₃+Q₄+Q₅+Q₆+Q₈.+U4+Q₁+Q₂+Q₃+Q₄₊Q₅+Q₆+Q₉.U4+Q₁+Q₃+Q₄+Q₅+Q₆+Q₇+Q₈,U4+Q₁+Q₃Q₄+Q₅+Q₆+Q₇+Q₉.+U4+Q₁+Q₄+Q₅+Q₆+Q₇+Q₈+Q₉.U4+Q₂+Q₃+Q₄+Q₅+Q₆+Q₇+Q₈+,U4+Q₂+Q₃+Q₄+Q₅+Q₆+Q₇+Q₉.+U4+Q₂+Q₃+Q₄+Q₅+Q₆+Q₈+Q₉,+U4+Q₂+Q₄+Q₅+Q₆+Q₇+Q₈+Q₉,+U4+Q₃+Q₄+Q₅+Q₆+Q₇+Q₈+Q₉,+U4+Q₁+Q₂+Q₃+Q₄+Q₅+Q₆+Q₇+Q₈,+U4+Q₁+Q₂+Q₃+Q₄+Q₅+Q₆+Q₇+Q₉,U4+Q₂+Q₃+Q₄+Q₅+Q₆+Q₇+Q₈+Q₉, or U4+Q₁+Q₂+Q₃Q₄ +Q₅+Q₆+Q₇+Q₈+Q₉,

Independently in some embodiments of A and R₆, and independently incombination with any embodiments of any other relevant substituentclasses, A and R₆ can be, independently, hydrogen, U₁, U₁+Q₁, U₁+Q₂,U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of B, C, and R^(b), and independentlyin combination with any embodiments of any other relevant substituentclasses, B, C, and R^(b) can be, independently, absent, hydrogen, U₁;U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of A and R₆, and independently incombination with any embodiments of any other relevant substituentclasses, A and R₆ can be, independently, hydrogen, amino, hydroxyl,thiol, oxo, phosphate, or J₁, Independently in some embodiments of A andR₆, and independently in combination with any embodiments of any otherrelevant substituent classes, A and R₆ can be, independently, hydrogen,amino, hydroxyl, thiol, oxo, phosphate, or J₂.

Independently in some embodiments of B, C, and R^(b), and independentlyin combination with any embodiments of any other relevant substituentclasses, B, C, and R^(b) can be, independently, absent, hydrogen, amino,hydroxyl, thiol, oxo, phosphate, or J₁.

Independently in some embodiments of B, C, and R^(b), and independentlyin combination with any embodiments of any other relevant substituentclasses, B, C, and R^(b) can be, independently, absent, hydrogen, amino,hydroxyl, thiol, oxo, phosphate, or J₂.

Independently in some embodiments of A and R₆, and independently incombination with any embodiments of any other relevant substituentclasses, A and R₆ can be, independently,

wherein y is an integer from 0-11; wherein w is an integer from 0-9;wherein k is an integer from 0 to 20;

wherein R^(d) and R^(e) are independently B, C, —B(—C)_(δ), R^(b), U₂,U₂+Q₁, U₂+Q₂, U₂+Q₃, U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃,U₂+Q₂+Q₄, U₂+Q₃+Q₄, U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄,and U₂+Q₁+Q₂+Q₃+Q₄, preferably U₂+Q₁+Q₃; or together with the carbonatom to which they are attached, form a 3- to 8-membered unsubstitutedor substituted carbocyclic or heterocyclic ring;

wherein X_(d) are independently absent, O, or S;

wherein R^(c) is B, C, —B(—C)_(δ), R^(b), absent, hydrogen, U₃, U₃+Q₁,U₃+Q₂, U₃+Q₃, U₃+Q₄, U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄,U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃, U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, andU₃+Q₁+Q₂+Q₃+Q₄, preferably U₃+Q₁+Q₃;

wherein R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are independently C, O, N, S,S(O), or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₃ are doubleor single according to valency, and wherein R₁₈ to R₂₃ are bound tonone, one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyB, C, absent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein IQ is 1%U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₄+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independently B,C, hydrogen, U₁; U₁+Q₁; U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃,U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄,U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃

Independently in some embodiments of B, and independently in combinationwith any embodiments of any other relevant substituent classes, B can be

wherein y is an integer from 0-11; wherein w is an integer from 0-9;wherein k is an integer from 0 to 20;

wherein R^(d) and R^(e) are independently C, R^(b), U₂, U₂+Q₁, U₂+Q₂,U₂+Q₃, U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃, U₂+Q₂+Q₄,U₂+Q₃+Q₄, U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄, andU₂+Q₁+Q₂+Q₃+Q₄, preferably U₂+Q₁+Q₃; or together with the carbon atom towhich they are attached, form a 3- to 8-membered unsubstituted orsubstituted carbocyclic or heterocyclic ring;

wherein X_(d) are independently absent, O, or S;

wherein R^(c) is C, R^(b), absent, hydrogen, U₃, U₃+Q₁; U₃+Q₂, U₃+Q₃,U₃+Q₄, U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄,U₃+Q₁+Q₂+Q₃, U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄,preferably U₃+Q₁+Q₃;

wherein R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are independently C, O, N, S,S(O), or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₃ are doubleor single according to valency, and wherein R₁₈ to R₂₃ are bound tonone, one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyC, R^(b), absent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₄ is U₁,U₁+Q₁; U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independently C,R^(b), hydrogen, U₁; U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃,U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄,U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃

Independently in some embodiments of R^(b), and independently incombination with any embodiments of any other relevant substituentclasses, R^(b) can be

wherein y is an integer from 0-11; wherein w is an integer from 0-9;wherein k is an integer from 0 to 20;

wherein R^(d) and R^(e) are independently C, U₂, U₂+Q₁, U₂+Q₂, U₂+Q₃,U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃, U₂+Q₂+Q₄, U₂+Q₃+Q₄,U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄, and U₂+Q₁+Q₂+Q₃+Q₄.preferably U₂+Q₁+Q₃; or together with the carbon atom to which they areattached, form a 3- to 8-membered unsubstituted or substitutedcarbocyclic or heterocyclic ring;

wherein X_(d) are independently absent, O, or S;

wherein R^(c) is C, absent, hydrogen, U₃, U₃+Q₁, U₃+Q₂, U₃+Q₃, U₃+Q₄,U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃,U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄, preferablyU₃+Q₁+Q₃;

wherein R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are independently C, O, N, S,S(O), or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₃ are doubleor single according to valency, and wherein R₁₈ to R₂₃ are bound tonone, one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)-, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyC, absent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein IQ is 1% U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₄+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independently C,hydrogen, U₁, U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄,U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄,U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

Independently in some embodiments of C, and independently in combinationwith any embodiments of any other relevant substituent classes C can be

wherein y is an integer from 0-11; wherein w is an integer from 0-9;wherein k is an integer from 0 to 20;

wherein R^(d) and R^(e) are independently U₂, U₂+Q₁, U₂+Q₂, U₂+Q₃,U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃, U₂+Q₂+Q₄, U₂+Q₃+Q₄,U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄, and U₂+Q₁+Q₂+Q₃+Q₄,preferably U₂+Q₁+Q₃; or together with the carbon atom to which they areattached, form a 3- to 8-membered unsubstituted or substitutedcarbocyclic or heterocyclic ring;

wherein X_(d) are independently absent, O, or S;

wherein R^(c) is absent, hydrogen, U₃, U₃+Q₁; U₃+Q₂, U₃+Q₃, U₃+Q₄,U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄, U₃+Q₄+Q₂+Q₃,U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄, preferablyU₃+Q₁+Q₃;

wherein R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are independently C, O, N, S,S(O), or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₃ are doubleor single according to valency, and wherein R₁₈ to R₂₃ are bound tonone, one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyabsent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₄ is U₁, U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independentlyhydrogen, U₁, U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄,U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄,U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

Independently in some embodiments of A and Rb, and independently incombination with any embodiments of any other relevant substituentclasses, A and R₆ can be, independently,

wherein y is an integer from 0-11; wherein w is an integer from 0-9;

wherein R^(d) and R^(e) are independently B, C, —B(—C)_(δ), R^(b), U₂,U₂+Q₁, U₂+Q₂, U₂+Q₃, U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃,U₂+Q₂+Q₄, U₂+Q₃+Q₄, U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄,and U₂+Q₁+Q₂+Q₃+Q₄, preferably U₂+Q₁+Q₃; or together with the carbonatom to which they are attached, form a 3- to 8-membered unsubstitutedor substituted carbocyclic or heterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are independently C, O, N, S,S(O), or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₃ are doubleor single according to valency, and wherein R₁₈ to R₂₃ are bound tonone, one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyB, C, absent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₄ isU₁,U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of B, and independently in combinationwith any embodiments of any other relevant substituent classes, B can be

wherein y is an integer from 0-11; wherein w is an integer from 0-9;

wherein R^(d) and R^(e) are independently C, R^(b), U₂, U₂+Q₁, U₂+Q₂,U₂+Q₃, U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃, U₂+Q₂+Q₄,U₂+Q₃+Q₄, U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄, andU₂+Q₁+Q₂+Q₃+Q₄, preferably U₂+Q₁+Q₃; or together with the carbon atom towhich they are attached, form a 3- to 8-membered unsubstituted orsubstituted carbocyclic or heterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are independently C, O, N, S,S(O), or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₃ are doubleor single according to valency, and wherein R₁₈ to R₂₃ are bound tonone, one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyC, R^(b), absent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein IG is U₁;U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of R^(b), and independently incombination with any embodiments of any other relevant substituentclasses, R^(b) can be

or

wherein y is an integer from 0-11; wherein w is an integer from 0-9;

wherein R^(d) and R^(e) are independently C, U₂, U₂+Q₁, U₂+Q₂, U₂+Q₃,U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃, U₂+Q₂+Q₄, U₂+Q₃+Q₄,U₂+Q₁+Q₂+Q₈, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄, and U₂+Q₁+Q₂+Q₃+Q₄.preferably U₂+Q₁+Q₃; or together with the carbon atom to which they areattached, form a 3- to 8-membered unsubstituted or substitutedcarbocyclic or heterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are independently C, O, N, S,S(O), or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₃ are doubleor single according to valency, and wherein R₁₈ to R₂₃ are bound tonone, one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyC, absent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₄ is U₁, U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of C, and independently in combinationwith any embodiments of any other relevant substituent classes, C can b

wherein y is an integer from 0-11; wherein w is an integer from 0-9;

wherein R^(d) and R^(e) are independently U₂, U₂+Q₁, U₂+Q₂, U₂+Q₃,U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃, U₂+Q₂+Q₄, U₂+Q₃+Q₄,U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄, and U₂+Q₁+Q₂+Q₃+Q₄,preferably U₂+Q₁+Q₃; or together with the carbon atom to which they areattached, form a 3- to 8-membered unsubstituted or substitutedcarbocyclic or heterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are independently C, O, N, S,S(O), or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₃ are doubleor single according to valency, and wherein R₁₈ to R₂₃ are bound tonone, one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyabsent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein IG is U₁; U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of A and IG, and independently incombination with any embodiments of any other relevant substituentclasses, A and IG can be, independently,

wherein w is an integer from 0-9;

wherein R^(d) and R^(e) are independently B, C, —B(—C)_(δ), R^(b), U₂,U₂+Q₁, U₂+Q₂, U₂+Q₃, U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃,U₂+Q₂+Q₄, U₂+Q₃+Q₄, U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄,and U₂+Q₁+Q₂+Q₃+Q₄, preferably U₂+Q₁+Q₃; or together with the carbonatom to which they are attached, form a 3- to 8-membered unsubstitutedor substituted carbocyclic or heterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are independently C, O, N, S, S(O),or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₂ are double orsingle according to valency, and wherein R₁₈ to R₂₂ are bound to none,one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyB, C, absent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₄ is U₁,U₁+Q₁; U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of B, and independently in combinationwith any embodiments of any other relevant substituent classes, B can be

wherein w is an integer from 0-9;

wherein R^(d) and R^(e) are independently C, R^(b), U₂, U₂+Q₁, U₂+Q₂,U₂+Q₃, U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃, U₂+Q₂+Q₄,U₂+Q₃+Q₄, U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄, andU₂+Q₁+Q₂+Q₃+Q₄, preferably U₂+Q₁+Q₃; or together with the carbon atom towhich they are attached, form a 3- to 8-membered unsubstituted orsubstituted carbocyclic or heterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are independently C, O, N, S, S(O),or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₂ are double orsingle according to valency, and wherein R₁₈ to R₂₂ are bound to none,one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)-, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyC, R^(b), absent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₄ is 1%U₁+Q₁; U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of R^(b), and independently incombination with any embodiments of any other relevant substituentclasses, R^(b) can be

wherein w is an integer from 0-9;

wherein R^(d) and R^(e) are independently C, U₂, U₂+Q₁, U₂+Q₂, U₂+Q₃,U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃, U₂+Q₂+Q₄, U₂+Q₃+Q₄,U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄, and U₂+Q₁+Q₂+Q₃+Q₄,preferably U₂+Q₁+Q₃; or together with the carbon atom to which they areattached, form a 3- to 8-membered unsubstituted or substitutedcarbocyclic or heterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are independently C, O, N, S, S(O),or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₂ are double orsingle according to valency, and wherein R₁₈ to R₂₂ are bound to none,one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyC, absent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₄ is U₁; U₁+Q₁;U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₄+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of C, and independently in combinationwith any embodiments of any other relevant substituent classes, C can be

wherein w is an integer from 0-9;

wherein R^(d) and R^(e) are independently U₂, U₂+Q₁, U₂+Q₂, U₂+Q₃,U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃, U₂+Q₂+Q₄, U₂+Q₃+Q₄,U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄, and U₂+Q₁+Q₂+Q₃+Q₄,preferably U₂+Q₁+Q₃; or together with the carbon atom to which they areattached, form a 3- to 8-membered unsubstituted or substitutedcarbocyclic or heterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are independently C, O, N, S, S(O),or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₂ are double orsingle according to valency, and wherein R₁₈ to R₂₂ are bound to none,one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyabsent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₄ is U₁; U₂+Q₁;U₂+Q₂, U₂+Q₃, U₂+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of A and R₆, and independently incombination with any embodiments of any other relevant substituentclasses, A and R₆ can be, independently,

wherein w is an integer from 0-9;

wherein R^(d) and R^(e) are independently B, C, —B(—C)_(δ), R^(b), U₂,U₂+Q₁, U₂+Q₂, U₂+Q₃, U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃,U₂+Q₂+Q₄, U₂+Q₃+Q₄, U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄,and U₂+Q₁+Q₂+Q₃+Q₄, preferably U₂+Q₁+Q₃; or together with the carbonatom to which they are attached, form a 3- to 8-membered unsubstitutedor substituted carbocyclic or heterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are independently C or N, whereinthe bonds between adjacent R₁₈ to R₂₂ are double or single according tovalency, wherein one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂are N and the others are C, and wherein R₁₈ to R₂₂ are bound to none,one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyB, C, absent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₄ is U₁,U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₂+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of B, and independently in combinationwith any embodiments of any other relevant substituent classes, B can be

wherein w is an integer from 0-9;

wherein R^(d) and R^(e) are independently C, R^(b), U₂, U₂+Q₁, U₂+Q₂,U₂+Q₃, U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃, U₂+Q₂+Q₄,U₂+Q₃+Q₄, U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄, andU₂+Q₁+Q₂+Q₃+Q₄, preferably U₂+Q₁+Q₃; or together with the carbon atom towhich they are attached, form a 3- to 8-membered unsubstituted orsubstituted carbocyclic or heterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are independently C or N, whereinthe bonds between adjacent R₁₈ to R₂₂ are double or single according tovalency, wherein one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂are N and the others are C, and wherein R₁₈ to R₂₂ are bound to none,one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyC, R^(b), absent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₄ is U₁,U₁+Q₁; U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of R^(b), and independently incombination with any embodiments of any other relevant substituentclasses, R^(b) can be

wherein w is an integer from 0-9;

wherein R^(d) and R^(e) are independently C, U₂, U₂+Q₁, U₂+Q₂, U₂+Q₃,U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃, U₂+Q₂+Q₄, U₂+Q₃+Q₄,U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄, and U₂+Q₁+Q₂+Q₃+Q₄,preferably U₂+Q₁+Q₃; or together with the carbon atom to which they areattached, form a 3- to 8-membered unsubstituted or substitutedcarbocyclic or heterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are independently C or N, whereinthe bonds between adjacent R₁₈ to R₂₂ are double or single according tovalency, wherein one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂are N and the others are C, and wherein R₁₈ to R₂₂ are bound to none,one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)-, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyC, absent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₄ is 1% U₁+Q₁;U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of C, and independently in combinationwith any embodiments of any other relevant substituent classes, C can be

wherein w is an integer from 0-9;

wherein R^(d) and R^(e) are independently U₂, U₂+Q₁, U₂+Q₂, U₂+Q₃,U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃, U₂+Q₂+Q₄, U₂+Q₃+Q₄,U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄, and U₂+Q₁+Q₂+Q₃+Q₄,preferably U₂+Q₁+Q₃; or together with the carbon atom to which they areattached, form a 3- to 8-membered unsubstituted or substitutedcarbocyclic or heterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are independently C or N, whereinthe bonds between adjacent R₁₈ to R₂₂ are double or single according tovalency, wherein one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂are N and the others are C, and wherein R₁₈ to R₂₂ are bound to none,one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyabsent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₄ is U₁; U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of A and R₆, and independently incombination with any embodiments of any other relevant substituentclasses, A and R₆ can be, independently,

wherein k is an integer from 0 to 20;

wherein X₄ are independently absent, O, or S;

wherein R^(c) is B, C, —B(—C)_(δ), R^(b), absent, hydrogen, U_(3j)U₃+Q₁,U₃+Q₂, U₃+Q₃, U₃+Q₄, U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄,U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃, U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, andU₃+Q₁+Q₂+Q₃+Q₄, preferably U₃+Q₁+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independently B,C, R^(b), hydrogen, U₁; U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃,U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄,U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃

Independently in some embodiments of B, and independently in combinationwith any embodiments of any other relevant substituent classes, B can be

wherein k is an integer from 0 to 20;

wherein X₄ are independently absent, O, or S;

wherein R^(c) is C, R^(b), absent, hydrogen U₃, U₃+Q₁; U₃+Q₂, U₃+Q₃,U₃+Q₄, U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄,U₃+Q₁+Q₂+Q₃, U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄,preferably U₃+Q₄+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independently C,R^(b), hydrogen, U₁, U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃,U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄,U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃

Independently in some embodiments of R^(b), and independently incombination with any embodiments of any other relevant substituentclasses, R^(b) can be

wherein k is an integer from 0 to 20;

wherein X_(d) are independently absent, O, or S;

wherein R^(c) is C, absent, hydrogen, U₃, U₃+Q₁, U₃+Q₂, U₃+Q₃, U₃+Q₄,U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃,U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄, preferablyU₃+Q₁+Q₃; and

wherein R₁₀, R₁₁, Rn, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independently C,hydrogen, U₁; U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄,U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄,U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

Independently in some embodiments of C, and independently in combinationwith any embodiments of any other relevant substituent classes, C can be

wherein k is an integer from 0 to 20;

wherein X_(d) are independently absent, O, or S;

wherein R^(c) is absent, hydrogen, U₃, U₃+Q₁; U₃+Q₂, U₃+Q₃, U₃+Q₄,U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃,U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄, preferablyU₃+Q₁+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independentlyhydrogen, U₁, U₁+Q₁; U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄,U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄,U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

Independently in some embodiments of A and R₆, and independently incombination with any embodiments of any other relevant substituentclasses, A and R₆ can be, independently,

wherein k is an integer from 0 to 20;

wherein X₄ are independently O or S;

wherein R^(c) is B, C, —B(—C)_(δ), R^(b), absent, hydrogen, U₃, U₃+Q₁,U₃+Q₂, U₃+Q₃, U₃+Q₄, U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄,U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃, U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, andU₃+Q₁+Q₂+Q₃+Q₄, preferably U₃+Q₁+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independently B,C, R^(b), hydrogen, U₁; U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃,U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄,U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃

Independently in some embodiments of B, and independently in combinationwith any embodiments of any other relevant substituent classes, B can be

wherein k is an integer from 0 to 20;

wherein X₄ are independently O or S;

wherein R^(c) is C, R^(b), absent, hydrogen, U₃, U₃+Q₁, U₃+Q₂, U₃+Q₃,U₃+Q₄, U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄,U₃+Q₁+Q₂+Q₃, U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄,preferably U₃+Q₁+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independently C,R^(b), hydrogen, U₁; U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃,U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄,U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃

Independently in some embodiments of R^(b), and independently incombination with any embodiments of any other relevant substituentclasses, R^(b) can be

wherein k is an integer from 0 to 20;

wherein X_(d) are independently O or S;

wherein R^(c) is C, absent, hydrogen, U₃, U₃+Q₁; U₃+Q₂, U₃+Q₃, U₃+Q₄,U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃,U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄, preferablyU₃+Q₁+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independently C,hydrogen, U₁; U₁+Q₁; U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄,U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄,U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

Independently in some embodiments of C, and independently in combinationwith any embodiments of any other relevant substituent classes, C can be

wherein k is an integer from 0 to 20;

wherein X₄ are independently O or S;

wherein R^(c) is absent, hydrogen, U₃, U₃+Q₁, U₃+Q₂, U₃+Q₃, U₃+Q₄,U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃,U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄, preferablyU₃+Q₁+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independentlyhydrogen, U₁, U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄,U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄,U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

Independently in some embodiments of A and R₆, and independently incombination with any embodiments of any other relevant substituentclasses, A and R₆ can be, independently,

wherein k is an integer from 1 to 20;

wherein X_(d) are O;

wherein R^(c) is B, C, —B(—C)_(δ), R^(b), U₃, U₃+Q₁; U₃+Q₂, U₃+Q₃,U₃+Q₄, U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄,U₃+Q₁+Q₂+Q₃, U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₄+Q₂+Q₃+Q₄,preferably U₃+Q₄+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independently B,C, R^(b), hydrogen, U₁; U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃,U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄,U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃Independently in some embodiments of B, and independently in combinationwith any embodiments of any other relevant substituent classes, B can be

wherein k is an integer from 1 to 20;

wherein X₄ are O;

wherein R^(c) is C, R^(b), absent, hydrogen, U₃, U₃+Q₁, U₃+Q₂, U₃+Q₃,U₃+Q₄, U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄,U₃+Q₁+Q₂+Q₃, U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄,preferably U₃+Q₁+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independently C,R^(b), hydrogen, U₁; U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃,U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄,U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃

Independently in some embodiments of R^(b), and independently incombination with any embodiments of any other relevant substituentclasses, R^(b) can be

wherein k is an integer from 1 to 20;

wherein X₄ are O;

wherein R^(c) is C, absent, hydrogen, U₃, U₃+Q₁, U₃+Q₂, U₃+Q₃, U₃+Q₄,U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃,U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄, preferablyU₃+Q₁+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independently C,hydrogen, U₁; U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄,U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄,U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

Independently in some embodiments of C, and independently in combinationwith any embodiments of any other relevant substituent classes, C can be

wherein k is an integer from 1 to 20;

wherein X_(d) are O;

wherein R^(c) is absent, hydrogen, U₃, U₃+Q₁; U₃+Q₂, U₃+Q₃, U₃+Q₄,U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃,U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄, preferablyU₃+Q₁+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independentlyhydrogen, U₁, U₁+Q₁; U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄,U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄,U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

In some embodiments, A is

wherein each k is, independently, an integer from 0 to 20;

wherein R^(c) is B;

wherein each X₄ is, independently, absent, O, or S; and

wherein each R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ is,independently, hydrogen, amino, hydroxyl, thiol, oxo, phosphate, or U;

wherein preferably k is 1, 2, 3, 4, 5, 6, or 7; each X₄ is O; and eachR₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ is, independently, hydrogen,C₁-C₃ alkyl, C₁-C₃ alkylene, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy,C₁-C₃ alkylamino, C₁-C₃ alkylthio;

wherein more preferably k is 2, 3, or 4; each X₄ is O; and each R₁₀,R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ is hydrogen; and

wherein most preferably A is —CH₂—CH₂-(0-CH₂—CH₂)₃—; and

B and C are, independently, absent, hydrogen, or an organic groupingcontaining any number of carbon atoms, 1-30 carbon atoms, 1-20 carbonatoms, or 1-14 carbon atoms, and optionally including one or moreheteroatoms such as oxygen, sulfur, or nitrogen grouping in linear,branched, or cyclic structural formats, representative organic groupingsbeing those present in U₁; U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂,U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃,U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferablyU₁+Q₁+Q₃.

In some embodiments, B is

wherein each w is, independently, an integer from 0-9;

wherein R^(d) is C;

wherein each R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is, independently, C, O, N, S,S(O), or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₂ are doubleor single according to valency, and wherein R₁₈ to R₂₂ are bound tonone, one, or two hydrogens according to valency;

preferably w is 1, 2, 3, or 4; and none, one, two, three, four, or fiveof R₁₈, R₁₀, R₂₀, R₂₁, and R₂₂ are N, none, one, two, three, four, orfive of R₁₈, R₁₀, R₂₀, R₂₁, and R₂₂ is O, and the others are C;

more preferably w is 1 or 2; and one, two, or three of R₁₈, R₁₀, R₂₀,R₂₁, and R₂₂ are N, none or one of R₁₈, R₁₀, R₂₀, R₂₁, and R₂₂ is O, andthe others are C;

even more preferably w is 1 or 2; and three of R₁₈, R₁₀, R₂₀, R₂₁, andR₂₂ are N, none of R₁₈, R₁₀, R₂₀, R₂₁, and R₂₂ is O, and the others areC; and

most preferably

wherein R₈ is hydrogen and R₉ is C;

A is hydrogen or an organic grouping containing any number of carbonatoms, 1-30 carbon atoms, 1-20 carbon atoms, or 1-14 carbon atoms, andoptionally including one or more heteroatoms such as oxygen, sulfur, ornitrogen grouping in linear, branched, or cyclic structural formats,representative organic groupings being those present in U₁, U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃; and

each C is, independently, absent, hydrogen, or an organic groupingcontaining any number of carbon atoms, 1-30 carbon atoms, 1-20 carbonatoms, or 1-14 carbon atoms, and optionally including one or moreheteroatoms such as oxygen, sulfur, or nitrogen grouping in linear,branched, or cyclic structural formats, representative organic groupingsbeing those present in U₁; U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂,U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃,U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferablyU₁+Q₁+Q₃.

In some embodiments, C is

wherein y is an integer from 0-11;

wherein each R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is, independently, C, O,N, S, S(O), or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₃ aredouble or single according to valency, and wherein R₁₈ to R₂₃ are boundto none, one, or two hydrogens according to valency;

wherein each R₂₄ is, independently, absent, —(CR₂₅R₂₅)_(p)—, or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein each p and q is,independently, an integer from 0 to 5, wherein X_(b) is absent, —O—,—S—, —S(O)—, —S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits,independently absent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein eachR₄ is, independently, J₂;

wherein each R^(e) is, independently, J₁;

preferably y is 0, 1, 2, 3, 4, or 5; none, one, two, three, four, five,or six of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are N, none, one, two, three,four, five, or six of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is O, none or oneis S(O)₂, and the others are C; each R₂₄ is, independently, absent,—(CR₂₅R₂₅)_(p)—, or —(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein each pis, independently, 0, 1, 2, or 3, each q is, independently, 0, 1, or 2,and X_(b) is O; and R^(e) is, independently, C₁-C₂ carbonyl, C₁-C₂carboxyl, C₁-C₂ amino, C₁-C₂ amido, C₁-C₂ sulfonyl, C₁-C₂ sulfonic acid,C₂-C₃ phosphoryl, or C₂-C₃ phosphonyl;

more preferably y is 0, 1, 2, or 3; none, one, two, or three of R₁₈,R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are N, none, one, or two of R₁₈, R₁₉, R₂₀,R₂₁, R₂₂, and R₂₃ is O, none or one is S(O)₂, and the others are C; eachR₂₄ is, independently, absent, —(CR₂₅R₂₅)_(p)—, or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein each p is, independently, 0or 1, each q is, independently, 0 or 1, and X_(b) is O; and R^(e) is,independently, C₁ carbonyl, C₁ carboxyl, C₁ amino, C₁ amido, C₁sulfonyl, C₁ sulfonic acid, C₂ phosphoryl, or C₂ phosphonyl; and evenmore preferably y is 0 or 1; none or one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, andR₂₃ are N, none or one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is O, none orone is S(O)₂, and the others are C; each R₂₄ is, independently, absent,—(CR₂₅R₂₅)_(p)—, or —(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein each pis, independently, 0 or 1, each q is, independently, 0 or 1, and X_(b)is O; and R^(e) is, independently, C₁ carbonyl, C₁ carboxyl, C₁ amino,or C₁ sulfonyl; and

most preferably C is

A is hydrogen or an organic grouping containing any number of carbonatoms, 1-carbon atoms, 1-20 carbon atoms, or 1-14 carbon atoms, andoptionally including one or more heteroatoms such as oxygen, sulfur, ornitrogen grouping in linear, branched, or cyclic structural formats,representative organic groupings being those present in 1% U₁+Q₁, U₁+Q₂,U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q_(x)+Q₂+Q₃+Q₄, preferably U₁+Q_(x)+Q₃; and

B is absent, hydrogen, or an organic grouping containing any number ofcarbon atoms, 1-30 carbon atoms, 1-20 carbon atoms, or 1-14 carbonatoms, and optionally including one or more heteroatoms such as oxygen,sulfur, or nitrogen grouping in linear, branched, or cyclic structuralformats, representative organic groupings being those present in U₁;U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

In some embodiments

A is

B is

each R₈, R₉, and C are, independently,

wherein each y is, independently, an integer from 0-11; wherein each wis, independently, an integer from 0-9; wherein each k is,independently, an integer from 0 to 20;

wherein in A, R^(c) is B,

wherein in B, R^(c), R^(d), and R^(e) are C,

wherein each X₄ is, independently, absent, O, or S;

wherein each R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is, independently, C, O,N, S, S(O), or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₃ aredouble or single according to valency, and wherein R₁₈ to R₂₃ are boundto none, one, or two hydrogens according to valency; and

wherein each R₂₄ is, independently, absent, —(CR₂₅R₂₅)_(p)—, or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein each p and q is,independently, an integer from 0 to 5, wherein X_(b) is absent, —O—,—S—, —S(O)—, —S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits,independently absent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein eachR₄ is, independently, U₁; U₁+Q₁; U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂,U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃,U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferablyU₁+Q₁+Q₃; and

wherein each R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ is,independently, hydrogen, U₁; U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂,U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃,U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferablyU₁+Q₁+Q₂+Q₃.

In some embodiments, each R₄ is, independently, J₂.

In some embodiments, each R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ is,independently, hydrogen, amino, hydroxyl, thiol, oxo, phosphate, or J₁.

In some embodiments, independently in each Formula IX, none, one, two,three, four, five, or six of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are N,none, one, two, three, four, five, or six of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,and R₂₃ is O, and the others are C. In some embodiments, independentlyin each Formula XIV, none, one, two, three, four, or five of R₁₈, R₁₉,R₂₀, R₂₁, and R₂₂ are N, none, one, two, three, four, or five of R₁₈,R₁₉, R₂₀, R₂₁, and R₂₂ is O, and the others are C.

In some embodiments, independently in each C, none, one, two, or threeof R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are N, none, one, two, or three ofR₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is O, and the others are C. In someembodiments, in B, three of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are N, none ofR₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is O, and the others are C.

In some embodiments, R₆ and A are —CH₂—Ar— or —CH₂—CH₂-(0-CH₂—CH₂)₃—; R₂is hydrogen; R₈ and C are hydrogen, methyl, or —CH₂—OH; and R₉ and C aremethyl, —COCH₃, -CH₇—N(CH₇—CH₃)₂,

In some embodiments, R₈ is hydrogen; and R₉ and C are

In some embodiments, R₈ is hydrogen; and R₉ and C are

In some embodiments, R₉ and C are methyl, —COCH₃, or —CH₂—N(CH₂—CH₃)₂.

In some embodiments, X is oxygen or NR₂, wherein R₂ is hydrogen, methyl,or —CH₂—CH₃; and R₁ is —CH₂—CH₂—CH₂—CH₂—OH,—CH₂—CH₂—(O—CH₂—CH₂)_(n)—O—CH₃, —CH₇—CH₇—O—CH₇—CH₇—OH.—(CH₂—CH₂)₃—NH—CH₃,

where n is an integer from 3 to 16.

Independently in some embodiments of R^(c), and independently incombination with any embodiments of any other relevant substituentclasses, R^(c) can be B, C, —B(—C)_(δ), R^(b), amino, hydroxyl, thiol,oxo, phosphate, or J.

Independently in some embodiments of R^(c), and independently incombination with any embodiments of any other relevant substituentclasses, R^(c) can be B, C, —B(—C)_(δ), R^(b), amino, hydroxyl, thiol,oxo, phosphate, or J₂.

Independently in some embodiments of R^(c), and independently incombination with any embodiments of any other relevant substituentclasses, R^(c) can be B, C, —B(—C)_(δ), R^(b), amino, hydroxyl, thiol,oxo, phosphate, or substituted or unsubstituted C₁-C₅ alkyl, C₁-C₅alkylene, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₁-C₅ alkoxy, C₁-C₅ alkylamino,Cr C₅ alkylthio, C₁-C₅ carbonyl, C₁-C₅ carboxyl, C₁-C₅ amido, C₁-C₅sulfonyl, C₁-C₅ sulfonic acid, C₁-C₅ sulfamoyl, C₁-C₅ sulfoxide, C₁-C₅phosphoryl, C₁-C₅ phosphonyl, C₁-C₄ alkyl, C₁-C₄ alkylene, C₂-C₄alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, C₁-C₄ alkylamino, C₁-C₄ alkylthio,C₁-C₄ carbonyl, C₁-C₄ carboxyl, C₁-C₄ amino, C₁-C₄ amido, C₁-C₄sulfonyl, C₁-C₄ sulfonic acid, C₁-C₄ sulfamoyl, C₁-C₄ sulfoxide, C₁-C₄phosphoryl, C₁-C₄ phosphonyl, C₁-C₃ alkyl, C₁-C₃ alkylene, C₂-C₃alkenyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, C₁-C₃ alkylamino, C₁-C₃ alkylthio,C₁-C₃ carbonyl, C₁-C₃ carboxyl, C₁-C₃ amino, C₁-C₃ amido, C₁-C₃sulfonyl, C₁-C₃ sulfonic acid, C₁-C₃ sulfamoyl, C₁-C₃ sulfoxide, C₁-C₃phosphoryl, C₁-C₃ phosphonyl, C₁-C₂ alkyl, C₁-C₂ alkylene, C₁-C₂ alkoxy,C₁-C₂ alkylamino, C₁-C₂ alkylthio, C₁-C₂ carbonyl, C₁-C₂ carboxyl, C₁-C₂amido, C₁-C₂ sulfonyl, C₁-C₂ sulfonic acid, C₁-C₂ sulfamoyl, C₁-C₂sulfoxide, C₁-C₂ phosphoryl, C₁-C₂ phosphonyl, C₀-C₅ sulfonyl, C₀-C₅sulfonic acid, C₀-C₅ sulfamoyl, C₀-C₅ sulfoxide, C₀-C₅ phosphoryl, C₀-C₅phosphonyl, C₀-C₄ sulfonyl, C₀-C₄ sulfonic acid, C₀-C₄ sulfamoyl, C₀-C₄sulfoxide, C₀-C₄ phosphoryl, C₀-C₄ phosphonyl, C₀-C₃ sulfonyl, C₀-C₃sulfonic acid, C₀-C₃ sulfamoyl, C₀-C₃ sulfoxide, C₀-C₃ phosphoryl, C₀-C₃phosphonyl, C₀-C₂ sulfonyl, C₀-C₂ sulfonic acid, C₀-C₂ sulfamoyl, C₀-C₂sulfoxide, C₀-C₂ phosphoryl, C₀-C₂ phosphonyl, C₀-C₁ sulfonyl, C₀-C₁sulfonic acid, C₀-C₁ sulfamoyl, C₀-C₁ sulfoxide, C₀-C₁ phosphoryl, C₀-C₁phosphonyl, C₅ alkyl, C₅ alkylene, C₅ alkenyl, C₅ alkynyl, C₅ alkoxy, C₅alkylamino, C₅ alkylthio, C₅ carbonyl, C₅ carboxyl, C₅ amido, C₅sulfonyl, C₅ sulfonic acid, C₅ sulfamoyl, C₅ sulfoxide, C₅ phosphoryl,C₅ phosphonyl, C₄ alkyl, C₄ alkylene, C₄ alkenyl, C₄ alkynyl, C₄ alkoxy,C₄ alkylamino, C₄ alkylthio, C₄ carbonyl, C₄ carboxyl, C₄ amido, C₄sulfonyl, C₄ sulfonic acid, C₄ sulfamoyl, C₄ sulfoxide, C₄ phosphoryl,C₄ phosphonyl, C₃ alkyl, C₃ alkylene, C₃ alkenyl, C₃ alkynyl, C₃ alkoxy,C₃ alkylamino, C₃ alkylthio, C₃ carbonyl, C₃ carboxyl, C₃ amido, C₃sulfonyl, C₃ sulfonic acid, C₃ sulfamoyl, C₃ sulfoxide, C₃ phosphoryl,C₃ phosphonyl, C₂ alkyl, C₂ alkylene, C₂ alkenyl, C₂ alkynyl, C₂ alkoxy,C₂ alkylamino, C₂ alkylthio, C₂ carbonyl, C₂ carboxyl, C₂ amido, C₂sulfonyl, C₂ sulfonic acid, C₂ sulfamoyl, C₂ sulfoxide, C₂ phosphoryl,C₂ phosphonyl, C₁ alkyl, C₁ alkylene, C₁ alkoxy, C₁ alkylamino, C₁alkylthio, C₁ carbonyl, C₁ carboxyl, C₁ amido, C₁ sulfonyl, C₁ sulfonicacid, C₁ sulfamoyl, C₁ sulfoxide, C₁ phosphoryl, C₁ phosphonyl, C₀sulfonyl, C₀ sulfonic acid, C₀ sulfamoyl, C₀ sulfoxide, C₀ phosphoryl,or C₀ phosphonyl.

Independently in some embodiments of R^(c), and independently incombination with any embodiments of any other relevant substituentclasses, R^(c) can be B, C, —B(—C)_(δ), R^(b), amino, hydroxyl, thiol,oxo, phosphate, or substituted or unsubstituted C₁-C₅ alkyl, C₁-C₅alkylene, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₁-C₅ alkoxy, C₁-C₅ alkylamino,C₁-C₅ alkylthio, C₁-C₄ alkyl, C₁-C₄ alkylene, C₂-C₄ alkenyl, C₂-C₄alkynyl, C₁-C₄ alkoxy, C₁-C₄ alkylamino, C₁-C₄ alkylthio, C₁-C₃ alkyl,C₁-C₃ alkylene, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, C₁-C₃alkylamino, C₁-C₃ alkylthio, C₁-C₂ alkyl, C₁-C₂ alkylene, C₁-C₂ alkoxy,C₁-C₂ alkylamino, C₁-C₂ alkylthio, C₁₀ alkyl, C₁₀ alkylene, C₁₀ alkenyl,C₁₀ alkynyl, C₁₀ alkoxy, C₁₀ alkylamino, C₁₀ alkylthio, C₉ alkyl, C₉alkylene, C₉ alkenyl, C₉ alkynyl, C₉ alkoxy, C₉ alkylamino, C₉alkylthio, C₈ alkyl, C₈ alkylene, C₈ alkenyl, C₈ alkynyl, C₈ alkoxy, C₈alkylamino, C₈ alkylthio, C₇ alkyl, C₇ alkylene, C₇ alkenyl, C₇ alkynyl,C₇ alkoxy, C₇ alkylamino, C₇ alkylthio, C₆ alkyl, C₆ alkylene, C₆alkenyl, C₆ alkynyl, C₆ alkoxy, C₆ alkylamino, C₆ alkylthio, C₅ alkyl,C₅ alkylene, C₅ alkenyl, C₅ alkynyl, C₅ alkoxy, C₅ alkylamino, C₅alkylthio, C₄ alkyl, C₄ alkylene, C₄ alkenyl, C₄ alkynyl, C₄ alkoxy, C₄alkylamino, C₄ alkylthio, C₃ alkyl, C₃ alkylene, C₃ alkenyl, C₃ alkynyl,C₃ alkoxy, C₃ alkylamino, C₃ alkylthio, C₂ alkyl, C₂ alkylene, C₂alkenyl, C₂ alkynyl, C₂ alkoxy, C₂ alkylamino, C₂ alkylthio, C₄ alkyl,C₄ alkylene, C₄ alkoxy, C₄ alkylamino, or C₄ alkylthio.

Independently in some embodiments of R^(c), and independently incombination with any embodiments of any other relevant substituentclasses, R^(c) can be B, C, —B(—C)_(δ), R^(b), amino, hydroxyl, thiol,oxo, phosphate, or substituted or unsubstituted C₁-C₄ alkyl, C₁-C₄alkylene, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, C₁-C₄ alkylamino,Cr C₄ alkylthio, C₁-C₄ carbonyl, C₁-C₄ carboxyl, C₁-C₄ amino, C₁-C₄amido, C₁-C₄ sulfonyl, C₁-C₄ sulfonic acid, C₁-C₄ sulfamoyl, C₁-C₄sulfoxide, C₁-C₄ phosphoryl, C₁-C₄ phosphonyl, C₁-C₃ alkyl, C₁-C₃alkylene, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, C₁-C₃ alkylamino,C₁-C₃ alkylthio, C₁-C₃ carbonyl, C₁-C₃ carboxyl, C₁-C₃ amino, C₁-C₃amido, C₁-C₃ sulfonyl, C₁-C₃ sulfonic acid, C₁-C₃ sulfamoyl, C₁-C₃sulfoxide, C₁-C₃ phosphoryl, C₁-C₃ phosphonyl, C₁-C₂ alkyl, C₁-C₂alkylene, C₁-C₂ alkoxy, C₁-C₂ alkylamino, C₁-C₂ alkylthio, C₁-C₂carbonyl, C₁-C₂ carboxyl, C₁-C₂ amido, C₁-C₂ sulfonyl, C₁-C₂ sulfonicacid, C₁-C₂ sulfamoyl, C₁-C₂ sulfoxide, C₁-C₂ phosphoryl, C₁-C₂phosphonyl, C₀-C₄ sulfonyl, C₀-C₄ sulfonic acid, C₀-C₄ sulfamoyl, C₀-C₄sulfoxide, C₀-C₄ phosphoryl, C₀-C₄ phosphonyl, C₀-C₃ sulfonyl, C₀-C₃sulfonic acid, C₀-C₃ sulfamoyl, C₀-C₃ sulfoxide, C₀-C₃ phosphoryl, C₀-C₃phosphonyl, C₀-C₂ sulfonyl, C₀-C₂ sulfonic acid, C₀-C₂ sulfamoyl, C₀-C₂sulfoxide, C₀-C₂ phosphoryl, C₀-C₂ phosphonyl, C₀-C₁ sulfonyl, C₀-C₁sulfonic acid, C₀-C₁ sulfamoyl, C₀-C₁ sulfoxide, C₀-C₁ phosphoryl, C₀-C₁phosphonyl, C₄ alkyl, C₄ alkylene, C₄ alkenyl, C₄ alkynyl, C₄ alkoxy, C₄alkylamino, C₄ alkylthio, C₄ carbonyl, C₄ carboxyl, C₄ amido, C₄sulfonyl, C₄ sulfonic acid, C₄ sulfamoyl, C₄ sulfoxide, C₄ phosphoryl,C₄ phosphonyl, C₃ alkyl, C₃ alkylene, C₃ alkenyl, C₃ alkynyl, C₃ alkoxy,C₃ alkylamino, C₃ alkylthio, C₃ carbonyl, C₃ carboxyl, C₃ amido, C₃sulfonyl, C₃ sulfonic acid, C₃ sulfamoyl, C₃ sulfoxide, C₃ phosphoryl,C₃ phosphonyl, C₂ alkyl, C₂ alkylene, C₂ alkenyl, C₂ alkynyl, C₂ alkoxy,C₂ alkylamino, C₂ alkylthio, C₂ carbonyl, C₂ carboxyl, C₂ amido, C₂sulfonyl, C₂ sulfonic acid, C₂ sulfamoyl, C₂ sulfoxide, C₂ phosphoryl,C₂ phosphonyl, C₁ alkyl, C₁ alkylene, C₁ alkoxy, C₁ alkylamino, C₄alkylthio, C₄ carbonyl, C₄ carboxyl, C₄ amido, C₄ sulfonyl, C₄ sulfonicacid, C₁ sulfamoyl, C₁ sulfoxide, C₁ phosphoryl, C₁ phosphonyl, C₀sulfonyl, C₀ sulfonic acid, C₀ sulfamoyl, C₀ sulfoxide, C₀ phosphoryl,or C₀ phosphonyl.

Independently in some embodiments of R^(c), and independently incombination with any embodiments of any other relevant substituentclasses, R^(c) can be B, C, —B(—C)_(δ), R^(b), amino, hydroxyl, thiol,oxo, phosphate, or substituted or unsubstituted C₁-C₄ alkyl, C₁-C₄alkylene, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, C₁-C₄ alkylamino,Cr C₄ alkylthio, C₁-C₃ alkyl, C₁-C₃ alkylene, C₂-C₃ alkenyl, C₂-C₃alkynyl, C₁-C₃ alkoxy, C₁-C₃ alkylamino, C₁-C₃ alkylthio, C₁-C₂ alkyl,C₁-C₂ alkylene, C₁-C₂ alkoxy, C₁-C₂ alkylamino, C₁-C₂ alkylthio, C₁₀alkyl, C₁₀ alkylene, C₁₀ alkenyl, C₁₀ alkynyl, C₁₀ alkoxy, C₁₀alkylamino, C₁₀ alkylthio, C₉ alkyl, C₉ alkylene, C₉ alkenyl, C₉alkynyl, C₉ alkoxy, C₉ alkylamino, C₉ alkylthio, C₈ alkyl, C₈ alkylene,C₈ alkenyl, C₈ alkynyl, C₈ alkoxy, C₈ alkylamino, C₈ alkylthio, C₇alkyl, C₇ alkylene, C₇ alkenyl, C₇ alkynyl, C₇ alkoxy, C₇ alkylamino, C₇alkylthio, C₆ alkyl, C₆ alkylene, C₆ alkenyl, C₆ alkynyl, C₆ alkoxy, C₆alkylamino, C₆ alkylthio, C₅ alkyl, C₅ alkylene, C₅ alkenyl, C₅ alkynyl,C₅ alkoxy, C₅ alkylamino, C₅ alkylthio, C₄ alkyl, C₄ alkylene, C₄alkenyl, C₄ alkynyl, C₄ alkoxy, C₄ alkylamino, C₄ alkylthio, C₃ alkyl,C₃ alkylene, C₃ alkenyl, C₃ alkynyl, C₃ alkoxy, C₃ alkylamino, C₃alkylthio, C₂ alkyl, C₂ alkylene, C₂ alkenyl, C₂ alkynyl, C₂ alkoxy, C₂alkylamino, C₂ alkylthio, C₁ alkyl, C₁ alkylene, C₁ alkoxy, C₁alkylamino, or C₁ alkylthio.

Independently in some embodiments of R^(c), and independently incombination with any embodiments of any other relevant substituentclasses, R^(c) can be B, C, —B(—C)_(δ), R^(b), amino, hydroxyl, thiol,oxo, phosphate, or substituted or unsubstituted C₁-C₃ alkyl, C₄-C₃alkylene, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, C₁-C₃ alkylamino,Cr C₃ alkylthio, C₁-C₃ carbonyl, C₁-C₃ carboxyl, C₁-C₃ amino, C₁-C₃amido, C₁-C₃ sulfonyl, C₁-C₃ sulfonic acid, C₁-C₃ sulfamoyl, C₁-C₃sulfoxide, C₁-C₃ phosphoryl, C₁-C₃ phosphonyl, C₁-C₂ alkyl, C₁-C₂alkylene, C₁-C₂ alkoxy, C₁-C₂ alkylamino, C₁-C₂ alkylthio, C₁-C₂carbonyl, C₁-C₂ carboxyl, C₁-C₂ amido, C₁-C₂ sulfonyl, C₁-C₂ sulfonicacid, C₁-C₂ sulfamoyl, C₁-C₂ sulfoxide, C₁-C₂ phosphoryl, C₁-C₂phosphonyl, C₀-C₃ sulfonyl, C₀-C₃ sulfonic acid, C₀-C₃ sulfamoyl, C₀-C₃sulfoxide, C₀-C₃ phosphoryl, C₀-C₃ phosphonyl, C₀-C₂ sulfonyl, C₀-C₂sulfonic acid, C₀-C₂ sulfamoyl, C₀-C₂ sulfoxide, C₀-C₂ phosphoryl, C₀-C₂phosphonyl, C₀-C₁ sulfonyl, C₀-C₁ sulfonic acid, C₀-C₁ sulfamoyl, C₀-C₁sulfoxide, C₀-C₁ phosphoryl, C₀-C₁ phosphonyl, C₃ alkyl, C₃ alkylene, C₃alkenyl, C₃ alkynyl, C₃ alkoxy, C₃ alkylamino, C₃ alkylthio, C₃carbonyl, C₃ carboxyl, C₃ amido, C₃ sulfonyl, C₃ sulfonic acid, C₃sulfamoyl, C₃ sulfoxide, C₃ phosphoryl, C₃ phosphonyl, C₂ alkyl, C₂alkylene, C₂ alkenyl, C₂ alkynyl, C₂ alkoxy, C₂ alkylamino, C₂alkylthio, C₂ carbonyl, C₂ carboxyl, C₂ amido, C₂ sulfonyl, C₂ sulfonicacid, C₂ sulfamoyl, C₂ sulfoxide, C₂ phosphoryl, C₂ phosphonyl, C₁alkyl, C₁ alkylene, C₁ alkoxy, C₁ alkylamino, C₁ alkylthio, C₁ carbonyl,C₁ carboxyl, C₁ amido, C₁ sulfonyl, C₁ sulfonic acid, C₁ sulfamoyl, C₁sulfoxide, C₁ phosphoryl, C₁ phosphonyl, C₀ sulfonyl, C₀ sulfonic acid,C₀ sulfamoyl, C₀ sulfoxide, C₀ phosphoryl, or C₀ phosphonyl.

Independently in some embodiments of R^(c), and independently incombination with any embodiments of any other relevant substituentclasses, R^(c) can be B, C, —B(—C)_(δ), R^(b), amino, hydroxyl, thiol,oxo, phosphate, or substituted or unsubstituted C₁-C₃ alkyl, C₁-C₃alkylene, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, C₁-C₃ alkylamino,Cr C₃ alkylthio, C₁-C₂ alkyl, C₁-C₂ alkylene, C₁-C₂ alkoxy, C₁-C₂alkylamino, C₁-C₂ alkylthio, C₁₀ alkyl, C₁₀ alkylene, C₁₀ alkenyl, C₁₀alkynyl, C₁₀ alkoxy, C₁₀ alkylamino, C₁₀ alkylthio, C₉ alkyl, C₉alkylene, C₉ alkenyl, C₉ alkynyl, C₉ alkoxy, C₉ alkylamino, C₉alkylthio, C₈ alkyl, C₈ alkylene, C₈ alkenyl, C₈ alkynyl, C₈ alkoxy, C₈alkylamino, C₈ alkylthio, C₇ alkyl, C₇ alkylene, C₇ alkenyl, C₇ alkynyl,C₇ alkoxy, C₇ alkylamino, C₇ alkylthio, C₆ alkyl, C₆ alkylene, C₆alkenyl, C₆ alkynyl, C₆ alkoxy, C₆ alkylamino, C₆ alkylthio, C₅ alkyl,C₅ alkylene, C₅ alkenyl, C₅ alkynyl, C₅ alkoxy, C₅ alkylamino, C₅alkylthio, C₄ alkyl, C₄ alkylene, C₄ alkenyl, C₄ alkynyl, C₄ alkoxy, C₄alkylamino, C₄ alkylthio, C₃ alkyl, C₃ alkylene, C₃ alkenyl, C₃ alkynyl,C₃ alkoxy, C₃ alkylamino, C₃ alkylthio, C₂ alkyl, C₂ alkylene, C₂alkenyl, C₂ alkynyl, C₂ alkoxy, C₂ alkylamino, C₂ alkylthio, C₄ alkyl,C₁ alkylene, C₁ alkoxy, C₁ alkylamino, or C₁ alkylthio.

Independently in some embodiments of R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆,and R₁₇, and independently in combination with any embodiments of anyother relevant substituent classes, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₁, R₁₆,and R₁₇ can be, independently, R^(b), hydrogen, amino, hydroxyl, thiol,oxo, phosphate, or J₁.

Independently in some embodiments of R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆,and R₁₇, and independently in combination with any embodiments of anyother relevant substituent classes, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆,and R₁₇ can be, independently, R^(b), hydrogen, amino, hydroxyl, thiol,oxo, phosphate, or substituted or J₂.

Independently in some embodiments of R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆,and R₁₇, and independently in combination with any embodiments of anyother relevant substituent classes, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆,and R₁₇ can be, independently, R^(b), hydrogen, amino, hydroxyl, thiol,oxo, phosphate, or substituted or unsubstituted C₁-C₅ alkyl, C₁-C₅alkylene, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₁-C₅ alkoxy, C₁-C₅ alkylamino,Cr C₅ alkylthio, C₁-C₅ carbonyl, C₁-C₅ carboxyl, C₁-C₅ amido, C₁-C₅sulfonyl, C₁-C₅ sulfonic acid, C₁-C₅ sulfamoyl, C₁-C₅ sulfoxide, C₁-C₅phosphoryl, C₁-C₅ phosphonyl, C₁-C₄ alkyl, C₁-C₄ alkylene, C₂-C₄alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, C₁-C₄ alkylamino, C₁-C₄ alkylthio,C₁-C₄ carbonyl, C₁-C₄ carboxyl, C₁-C₄ amino, C₁-C₄ amido, C₁-C₄sulfonyl, C₁-C₄ sulfonic acid, C₁-C₄ sulfamoyl, C₁-C₄ sulfoxide, C₁-C₄phosphoryl, C₁-C₄ phosphonyl, C₁-C₃ alkyl, C₁-C₃ alkylene, C₂-C₃alkenyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, C₁-C₃ alkylamino, C₁-C₃ alkylthio,C₁-C₃ carbonyl, C₁-C₃ carboxyl, C₁-C₃ amino, C₁-C₃ amido, C₁-C₃sulfonyl, C₁-C₃ sulfonic acid, C₁-C₃ sulfamoyl, C₁-C₃ sulfoxide, C₁-C₃phosphoryl, C₁-C₃ phosphonyl, C₁-C₂ alkyl, C₁-C₂ alkylene, C₁-C₂ alkoxy,C₁-C₂ alkylamino, C₁-C₂ alkylthio, C₁-C₂ carbonyl, C₁-C₂ carboxyl, C₁-C₂amido, C₁-C₂ sulfonyl, C₁-C₂ sulfonic acid, C₁-C₂ sulfamoyl, C₁-C₂sulfoxide, C₁-C₂ phosphoryl, C₁-C₂ phosphonyl, C₀-C₅ sulfonyl, C₀-C₅sulfonic acid, C₀-C₅ sulfamoyl, C₀-C₅ sulfoxide, C₀-C₅ phosphoryl, C₀-C₅phosphonyl, C₀-C₄ sulfonyl, C₀-C₄ sulfonic acid, C₀-C₄ sulfamoyl, C₀-C₄sulfoxide, C₀-C₄ phosphoryl, C₀-C₄ phosphonyl, C₀-C₃ sulfonyl, C₀-C₃sulfonic acid, C₀-C₃ sulfamoyl, C₀-C₃ sulfoxide, C₀-C₃ phosphoryl, C₀-C₃phosphonyl, C₀-C₂ sulfonyl, C₀-C₂ sulfonic acid, C₀-C₂ sulfamoyl, C₀-C₂sulfoxide, C₀-C₂ phosphoryl, C₀-C₂ phosphonyl, C₀-C₁ sulfonyl, C₀-C₁sulfonic acid, C₀-C₁ sulfamoyl, C₀-C₁ sulfoxide, C₀-C₁ phosphoryl, C₀-C₁phosphonyl, C₅ alkyl, C₅ alkylene, C₅ alkenyl, C₅ alkynyl, C₅ alkoxy, C₅alkylamino, C₅ alkylthio, C₅ carbonyl, C₅ carboxyl, C₅ amido, C₅sulfonyl, C₅ sulfonic acid, C₅ sulfamoyl, C₅ sulfoxide, C₅ phosphoryl,C₅ phosphonyl, C₄ alkyl, C₄ alkylene, C₄ alkenyl, C₄ alkynyl, C₄ alkoxy,C₄ alkylamino, C₄ alkylthio, C₄ carbonyl, C₄ carboxyl, C₄ amido, C₄sulfonyl, C₄ sulfonic acid, C₄ sulfamoyl, C₄ sulfoxide, C₄ phosphoryl,C₄ phosphonyl, C₃ alkyl, C₃ alkylene, C₃ alkenyl, C₃ alkynyl, C₃ alkoxy,C₃ alkylamino, C₃ alkylthio, C₃ carbonyl, C₃ carboxyl, C₃ amido, C₃sulfonyl, C₃ sulfonic acid, C₃ sulfamoyl, C₃ sulfoxide, C₃ phosphoryl,C₃ phosphonyl, C₂ alkyl, C₂ alkylene, C₂ alkenyl, C₂ alkynyl, C₂ alkoxy,C₂ alkylamino, C₂ alkylthio, C₂ carbonyl, C₂ carboxyl, C₂ amido, C₂sulfonyl, C₂ sulfonic acid, C₂ sulfamoyl, C₂ sulfoxide, C₂ phosphoryl,C₂ phosphonyl, C₄ alkyl, C₄ alkylene, C₄ alkoxy, C₄ alkylamino, C₄alkylthio, C₄ carbonyl, C₄ carboxyl, C₄ amido, C₄ sulfonyl, C₄ sulfonicacid, C₄ sulfamoyl, C₄ sulfoxide, C₁ phosphoryl, C₁ phosphonyl, C₀sulfonyl, C₀ sulfonic acid, C₀ sulfamoyl, C₀ sulfoxide, C₀ phosphoryl,or C₀ phosphonyl.

Independently in some embodiments of R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆,and R₁₇, and independently in combination with any embodiments of anyother relevant substituent classes, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆,and R₁₇ can be, independently, R^(b), hydrogen, amino, hydroxyl, thiol,oxo, phosphate, or substituted or unsubstituted C₁-C₅ alkyl, C₁-C₅alkylene, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₁-C₅ alkoxy, C₁-C₅ alkylamino,Cr C₅ alkylthio, C₁-C₄ alkyl, C₁-C₄ alkylene, C₂-C₄ alkenyl, C₂-C₄alkynyl, C₁-C₄ alkoxy, C₁-C₄ alkylamino, C₁-C₄ alkylthio, C₁-C₃ alkyl,C₁-C₃ alkylene, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, C₁-C₃alkylamino, C₁-C₃ alkylthio, C₁-C₂ alkyl, C₁-C₂ alkylene, C₁-C₂ alkoxy,C₁-C₂ alkylamino, C₁-C₂ alkylthio, C₁₀ alkyl, C₁₀ alkylene, C₁₀ alkenyl,C₁₀ alkynyl, C₁₀ alkoxy, C₁₀ alkylamino, C₁₀ alkylthio, C₉ alkyl, C₉alkylene, C₉ alkenyl, C₉ alkynyl, C₉ alkoxy, C₉ alkylamino, C₉alkylthio, C₈ alkyl, C₈ alkylene, C₈ alkenyl, C₈ alkynyl, C₈ alkoxy, C₈alkylamino, C₈ alkylthio, C₇ alkyl, C₇ alkylene, C₇ alkenyl, C₇ alkynyl,C₇ alkoxy, C₇ alkylamino, C₇ alkylthio, C₆ alkyl, C₆ alkylene, C₆alkenyl, C₆ alkynyl, C₆ alkoxy, C₆ alkylamino, C₆ alkylthio, C₅ alkyl,C₅ alkylene, C₅ alkenyl, C₅ alkynyl, C₅ alkoxy, C₅ alkylamino, C₅alkylthio, C₄ alkyl, C₄ alkylene, C₄ alkenyl, C₄ alkynyl, C₄ alkoxy, C₄alkylamino, C₄ alkylthio, C₃ alkyl, C₃ alkylene, C₃ alkenyl, C₃ alkynyl,C₃ alkoxy, C₃ alkylamino, C₃ alkylthio, C₂ alkyl, C₂ alkylene, C₂alkenyl, C₂ alkynyl, C₂ alkoxy, C₂ alkylamino, C₂ alkylthio, C₄ alkyl,C₄ alkylene, C₄ alkoxy, C₄ alkylamino, or C₄ alkylthio.

Independently in some embodiments of R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆,and R₁₇, and independently in combination with any embodiments of anyother relevant substituent classes, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆,and R₁₇ can be, independently, R^(b), hydrogen, amino, hydroxyl, thiol,oxo, phosphate, or substituted or unsubstituted C₁-C₄ alkyl, C₁-C₄alkylene, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, C₁-C₄ alkylamino,Cr C₄ alkylthio, C₁-C₄ carbonyl, C₁-C₄ carboxyl, C₁-C₄ amino, C₁-C₄amido, C₁-C₄ sulfonyl, C₁-C₄ sulfonic acid, C₁-C₄ sulfamoyl, C₁-C₄sulfoxide, C₁-C₄ phosphoryl, C₁-C₄ phosphonyl, C₁-C₃ alkyl, C₁-C₃alkylene, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, C₁-C₃ alkylamino,C₁-C₃ alkylthio, C₁-C₃ carbonyl, C₁-C₃ carboxyl, C₁-C₃ amino, C₁-C₃amido, C₁-C₃ sulfonyl, C₁-C₃ sulfonic acid, C₁-C₃ sulfamoyl, C₁-C₃sulfoxide, C₁-C₃ phosphoryl, C₁-C₃ phosphonyl, C₁-C₂ alkyl, C₁-C₂alkylene, C₁-C₂ alkoxy, C₁-C₂ alkylamino, C₁-C₂ alkylthio, C₁-C₂carbonyl, C₁-C₂ carboxyl, C₁-C₂ amido, C₁-C₂ sulfonyl, C₁-C₂ sulfonicacid, C₁-C₂ sulfamoyl, C₁-C₂ sulfoxide, C₁-C₂ phosphoryl, C₁-C₂phosphonyl, C₀-C₄ sulfonyl, C₀-C₄ sulfonic acid, C₀-C₄ sulfamoyl, C₀-C₄sulfoxide, C₀-C₄ phosphoryl, C₀-C₄ phosphonyl, C₀-C₃ sulfonyl, C₀-C₃sulfonic acid, C₀-C₃ sulfamoyl, C₀-C₃ sulfoxide, C₀-C₃ phosphoryl, C₀-C₃phosphonyl, C₀-C₂ sulfonyl, C₀-C₂ sulfonic acid, C₀-C₂ sulfamoyl, C₀-C₂sulfoxide, C₀-C₂ phosphoryl, C₀-C₂ phosphonyl, C₀-C₁ sulfonyl, C₀-C₁sulfonic acid, C₀-C₁ sulfamoyl, C₀-C₁ sulfoxide, C₀-C₁ phosphoryl, C₀-C₁phosphonyl, C₄ alkyl, C₄ alkylene, C₄ alkenyl, C₄ alkynyl, C₄ alkoxy, C₄alkylamino, C₄ alkylthio, C₄ carbonyl, C₄ carboxyl, C₄ amido, C₄sulfonyl, C₄ sulfonic acid, C₄ sulfamoyl, C₄ sulfoxide, C₄ phosphoryl,C₄ phosphonyl, C₃ alkyl, C₃ alkylene, C₃ alkenyl, C₃ alkynyl, C₃ alkoxy,C₃ alkylamino, C₃ alkylthio, C₃ carbonyl, C₃ carboxyl, C₃ amido, C₃sulfonyl, C₃ sulfonic acid, C₃ sulfamoyl, C₃ sulfoxide, C₃ phosphoryl,C₃ phosphonyl, C₂ alkyl, C₂ alkylene, C₂ alkenyl, C₂ alkynyl, C₂ alkoxy,C₂ alkylamino, C₂ alkylthio, C₂ carbonyl, C₂ carboxyl, C₂ amido, C₂sulfonyl, C₂ sulfonic acid, C₂ sulfamoyl, C₂ sulfoxide, C₂ phosphoryl,C₂ phosphonyl, C₁ alkyl, C₁ alkylene, C₁ alkoxy, C₁ alkylamino, C₁alkylthio, C₁ carbonyl, C₁ carboxyl, C₁ amido, C₁ sulfonyl, C₁ sulfonicacid, C₁ sulfamoyl, C₁ sulfoxide, C₁ phosphoryl, C₁ phosphonyl, C₀sulfonyl, C₀ sulfonic acid, C₀ sulfamoyl, C₀ sulfoxide, C₀ phosphoryl,or C₀ phosphonyl.

Independently in some embodiments of R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆,and R₁₇, and independently in combination with any embodiments of anyother relevant substituent classes, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆,and R₁₇ can be, independently, R^(b), hydrogen, amino, hydroxyl, thiol,oxo, phosphate, or substituted or unsubstituted C₁-C₄ alkyl, C₁-C₄alkylene, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, C₁-C₄ alkylamino,C₁-C₄ alkylthio, C₁-C₃ alkyl, C₁-C₃ alkylene, C₂-C₃ alkenyl, C₂-C₃alkynyl, C₁-C₃ alkoxy, C₁-C₃ alkylamino, C₁-C₃ alkylthio, C₁-C₂ alkyl,C₁-C₂ alkylene, C₁-C₂ alkoxy, C₁-C₂ alkylamino, C₁-C₂ alkylthio, C₁₀alkyl, C₁₀ alkylene, C₁₀ alkenyl, C₁₀ alkynyl, C₁₀ alkoxy, C₁₀alkylamino, C₁₀ alkylthio, C₉ alkyl, C₉ alkylene, C₉ alkenyl, C₉alkynyl, C₉ alkoxy, C₉ alkylamino, C₉ alkylthio, C₈ alkyl, C₈ alkylene,C₈ alkenyl, C₈ alkynyl, C₈ alkoxy, C₈ alkylamino, C₈ alkylthio, C₇alkyl, C₇ alkylene, C₇ alkenyl, C₇ alkynyl, C₇ alkoxy, C₇ alkylamino, C₇alkylthio, C₆ alkyl, C₆ alkylene, C₆ alkenyl, C₆ alkynyl, C₆ alkoxy, C₆alkylamino, C₆ alkylthio, C₅ alkyl, C₅ alkylene, C₅ alkenyl, C₅ alkynyl,C₅ alkoxy, C₅ alkylamino, C₅ alkylthio, C₄ alkyl, C₄ alkylene, C₄alkenyl, C₄ alkynyl, C₄ alkoxy, C₄ alkylamino, C₄ alkylthio, C₃ alkyl,C₃ alkylene, C₃ alkenyl, C₃ alkynyl, C₃ alkoxy, C₃ alkylamino, C₃alkylthio, C₂ alkyl, C₂ alkylene, C₂ alkenyl, C₂ alkynyl, C₂ alkoxy, C₂alkylamino, C₂ alkylthio, C₄ alkyl, C₄ alkylene, C₄ alkoxy, C₄alkylamino, or C₁ alkylthio.

Independently in some embodiments of R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆,and R₁₇, and independently in combination with any embodiments of anyother relevant substituent classes, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆,and R₁₇ can be, independently, R^(b), hydrogen, amino, hydroxyl, thiol,oxo, phosphate, or substituted or unsubstituted C₁-C₃ alkyl, C₁-C₃alkylene, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, C₁-C₃ alkylamino,Cr C₃ alkylthio, C₁-C₃ carbonyl, C₁-C₃ carboxyl, C₁-C₃ amino, C₁-C₃amido, C₁-C₃ sulfonyl, C₁-C₃ sulfonic acid, C₁-C₃ sulfamoyl, C₁-C₃sulfoxide, C₁-C₃ phosphoryl, C₁-C₃ phosphonyl, C₁-C₂ alkyl, C₁-C₂alkylene, C₁-C₂ alkoxy, C₁-C₂ alkylamino, C₁-C₂ alkylthio, C₁-C₂carbonyl, C₁-C₂ carboxyl, C₁-C₂ amido, C₁-C₂ sulfonyl, C₁-C₂ sulfonicacid, C₁-C₂ sulfamoyl, C₁-C₂ sulfoxide, C₁-C₂ phosphoryl, C₁-C₂phosphonyl, C₀-C₃ sulfonyl, C₀-C₃ sulfonic acid, C₀-C₃ sulfamoyl, C₀-C₃sulfoxide, C₀-C₃ phosphoryl, C₀-C₃ phosphonyl, C₀-C₂ sulfonyl, C₀-C₂sulfonic acid, C₀-C₂ sulfamoyl, C₀-C₂ sulfoxide, C₀-C₂ phosphoryl, C₀-C₂phosphonyl, C₀-C₁ sulfonyl, C₀-C₁ sulfonic acid, C₀-C₁ sulfamoyl, C₀-C₁sulfoxide, C₀-C₁ phosphoryl, C₀-C₁ phosphonyl, C₃ alkyl, C₃ alkylene, C₃alkenyl, C₃ alkynyl, C₃ alkoxy, C₃ alkylamino, C₃ alkylthio, C₃carbonyl, C₃ carboxyl, C₃ amido, C₃ sulfonyl, C₃ sulfonic acid, C₃sulfamoyl, C₃ sulfoxide, C₃ phosphoryl, C₃ phosphonyl, C₂ alkyl, C₂alkylene, C₂ alkenyl, C₂ alkynyl, C₂ alkoxy, C₂ alkylamino, C₂alkylthio, C₂ carbonyl, C₂ carboxyl, C₂ amido, C₂ sulfonyl, C₂ sulfonicacid, C₂ sulfamoyl, C₂ sulfoxide, C₂ phosphoryl, C₂ phosphonyl, C₁alkyl, C₁ alkylene, C₁ alkoxy, C₁ alkylamino, C₁ alkylthio, C₁ carbonyl,C₁ carboxyl, C₁ amido, C₁ sulfonyl, C₁ sulfonic acid, C₁ sulfamoyl, C₁sulfoxide, C₁ phosphoryl, C₁ phosphonyl, C₀ sulfonyl, C₀ sulfonic acid,C₀ sulfamoyl, C₀ sulfoxide, C₀ phosphoryl, or C₀ phosphonyl.

Independently in some embodiments of R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆,and R₁₇, and independently in combination with any embodiments of anyother relevant substituent classes, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆,and R₁₇ can be, independently, R^(b), hydrogen, amino, hydroxyl, thiol,oxo, phosphate, or substituted or unsubstituted C₁-C₃ alkyl, C₁-C₃alkylene, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, C₁-C₃ alkylamino,Cr C₃ alkylthio, C₁-C₂ alkyl, C₁-C₂ alkylene, C₁-C₂ alkoxy, C₁-C₂alkylamino, C₁-C₂ alkylthio, C₁₀ alkyl, C₁₀ alkylene, C₁₀ alkenyl, C₁₀alkynyl, C₁₀ alkoxy, C₁₀ alkylamino, C₁₀ alkylthio, C₉ alkyl, C₉alkylene, C₉ alkenyl, C₉ alkynyl, C₉ alkoxy, C₉ alkylamino, C₉alkylthio, C₈ alkyl, C₈ alkylene, C₈ alkenyl, C₈ alkynyl, C₈ alkoxy, C₈alkylamino, C₈ alkylthio, C₇ alkyl, C₇ alkylene, C₇ alkenyl, C₇ alkynyl,C₇ alkoxy, C₇ alkylamino, C₇ alkylthio, C₆ alkyl, C₆ alkylene, C₆alkenyl, C₆ alkynyl, C₆ alkoxy, C₆ alkylamino, C₆ alkylthio, C₅ alkyl,C₅ alkylene, C₅ alkenyl, C₅ alkynyl, C₅ alkoxy, C₅ alkylamino, C₅alkylthio, C₄ alkyl, C₄ alkylene, C₄ alkenyl, C₄ alkynyl, C₄ alkoxy, C₄alkylamino, C₄ alkylthio, C₃ alkyl, C₃ alkylene, C₃ alkenyl, C₃ alkynyl,C₃ alkoxy, C₃ alkylamino, C₃ alkylthio, C₂ alkyl, C₂ alkylene, C₂alkenyl, C₂ alkynyl, C₂ alkoxy, C₂ alkylamino, C₂ alkylthio, C₄ alkyl,C₁ alkylene, C₁ alkoxy, C₁ alkylamino, or C₁ alkylthio.

Independently in some embodiments of 5, and independently in combinationwith any embodiments of any other relevant substituent classes, 5 can bean integer from 1 to 30, 2 to 30, 3 to 30, 4 to 30, 5 to 30, 6 to 30, 7to 30, 8 to 30, 9 to 30, 10 to 30, 11 to 30, 12 to 30, 13 to 30, 14 to30, 15 to 30, 16 to 30, 17 to 30, 18 to 30, 19 to 30, 20 to 30, 21 to30, 22 to 30, 23 to 30, 24 to 30, 25 to 30, 26 to 30, 27 to 30, 28 to30, 29 to 30, 1 to 29, 2 to 29, 3 to 29, 4 to 29, 5 to 29, 6 to 29, 7 to29, 8 to 29, 9 to 29, 10 to 29, 11 to 29, 12 to 29, 13 to 29, 14 to 29,15 to 29, 16 to 29, 17 to 29, 18 to 29, 19 to 29, 20 to 29, 21 to 29, 22to 29, 23 to 29, 24 to 29, 25 to 29, 26 to 29, 27 to 29, 28 to 29, 1 to28, 2 to 28, 3 to 28, 4 to 28, 5 to 28, 6 to 28, 7 to 28, 8 to 28, 9 to28, 10 to 28, 11 to 28, 12 to 28, 13 to 28, 14 to 28, 15 to 28, 16 to28, 17 to 28, 18 to 28, 19 to 28, 20 to 28, 21 to 28, 22 to 28, 23 to28, 24 to 28, 25 to 28, 26 to 28, 27 to 28, 1 to 27, 2 to 27, 3 to 27, 4to 27, 5 to 27, 6 to 27, 7 to 27, 8 to 27, 9 to 27, 10 to 27, 11 to 27,12 to 27, 13 to 27, 14 to 27, 15 to 27, 16 to 27, 17 to 27, 18 to 27, 19to 27, 20 to 27, 21 to 27, 22 to 27, 23 to 27, 24 to 27, 25 to 27, 26 to27, 1 to 26, 2 to 26, 3 to 26, 4 to 26, 5 to 26, 6 to 26, 7 to 26, 8 to26, 9 to 26, to 26, 11 to 26, 12 to 26, 13 to 26, 14 to 26, 15 to 26, 16to 26, 17 to 26, 18 to 26, 19 to 26, 20 to 26, 21 to 26, 22 to 26, 23 to26, 24 to 26, 25 to 26, 1 to 25, 2 to 25, 3 to 25, 4 to 25, 5 to 25, 6to 25, 7 to 25, 8 to 25, 9 to 25, 10 to 25, 11 to 25, 12 to 25, 13 to25, 14 to 25, 15 to 25, 16 to 25, 17 to 25, 18 to 25, 19 to 25, 20 to25, 21 to 25, 22 to 25, 23 to 25, 24 to 25, 1 to 24, 2 to 24, 3 to 24, 4to 24, 5 to 24, 6 to 24, 7 to 24, 8 to 24, 9 to 24, 10 to 24, 11 to 24,12 to 24, 13 to 24, 14 to 24, 15 to 24, 16 to 24, 17 to 24, 18 to 24, 19to 24, 20 to 24, 21 to 24, 22 to 24, 23 to 24, 1 to 23, 2 to 23, 3 to23, 4 to 23, 5 to 23, 6 to 23, 7 to 23, 8 to 23, 9 to 23, 10 to 23, 11to 23, 12 to 23, 13 to 23, 14 to 23, 15 to 23, 16 to 23, 17 to 23, 18 to23, 19 to 23, 20 to 23, 21 to 23, 22 to 23, 1 to 22, 2 to 22, 3 to 22, 4to 22, 5 to 22, 6 to 22, 7 to 22, 8 to 22, 9 to 22, 10 to 22, 11 to 22,12 to 22, 13 to 22, 14 to 22, 15 to 22, 16 to 22, 17 to 22, 18 to 22, 19to 22, 20 to 22, 21 to 22, 1 to 21, 2 to 21, 3 to 21, 4 to 21, 5 to 21,6 to 21, 7 to 21, 8 to 21, 9 to 21, 10 to 21, 11 to 21, 12 to 21, 13 to21, 14 to 21, 15 to 21, 16 to 21, 17 to 21, 18 to 21, 19 to 21, 20 to21, 1 to 20, 2 to 20, 3 to 20, 4 to 20, 5 to 20, 6 to 20, 7 to 20, 8 to20, 9 to 20, 10 to 20, 11 to 20, 12 to 20, 13 to 20, 14 to 20, 15 to 20,16 to 20, 17 to 20, 18 to 20, 19 to 20, 1 to 19, 2 to 19, 3 to 19, 4 to19, 5 to 19, 6 to 19, 7 to 19, 8 to 19, 9 to 19, 10 to 19, 11 to 19, 12to 19, 13 to 19, 14 to 19, 15 to 19, 16 to 19, 17 to 19, 18 to 19, 1 to18, 2 to 18, 3 to 18, 4 to 18, 5 to 18, 6 to 18, 7 to 18, 8 to 18, 9 to18, 10 to 18, 11 to 18, 12 to 18, 13 to 18, 14 to 18, 15 to 18, 16 to18, 17 to 18, 1 to 17, 2 to 17, 3 to 17, 4 to 17, 5 to 17, 6 to 17, 7 to17, 8 to 17, 9 to 17, to 17, 11 to 17, 12 to 17, 13 to 17, 14 to 17, 15to 17, 16 to 17, 1 to 16, 2 to 16, 3 to 16, 4 to 16, 5 to 16, 6 to 16, 7to 16, 8 to 16, 9 to 16, 10 to 16, 11 to 16, 12 to 16, 13 to 16, 14 to16, 15 to 16, 1 to 15, 2 to 15, 3 to 15, 4 to 15, 5 to 15, 6 to 15, 7 to15, 8 to 15, 9 to 15, 10 to 15, 11 to 15, 12 to 15, 13 to 15, 14 to 15,1 to 14, 2 to 14, 3 to 14, 4 to 14, 5 to 14, 6 to 14, 7 to 14, 8 to 14,9 to 14, 10 to 14, 11 to 14, 12 to 14, 13 to 14, 1 to 13, 2 to 13, 3 to13, 4 to 13, 5 to 13, 6 to 13, 7 to 13, 8 to 13, 9 to 13, 10 to 13, 11to 13, 12 to 13, 1 to 12, 2 to 12, 3 to 12, 4 to 12, 5 to 12, 6 to 12, 7to 12, 8 to 12, 9 to 12, 10 to 12, 11 to 12, 1 to 11, 2 to 11, 3 to 11,4 to 11, 5 to 11, 6 to 11, 7 to 11, 8 to 11, 9 to 11, 10 to 11, 1 to 10,2 to 10, 3 to 10, 4 to 10, 5 to 10, 6 to 10, 7 to 10, 8 to 10, 9 to 10,1 to 9, 2 to 9, 3 to 9, 4 to 9, 5 to 9, 6 to 9, 7 to 9, 8 to 9, 1 to 8,2 to 8, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 7 to 8, 1 to 7, 2 to 7, 3 to 7,4 to 7, 5 to 7, 6 to 7, 1 to 6, 2 to 6, 3 to 6, 4 to 6, 5 to 6, 1 to 5,2 to 5, 3 to 5, 4 to 5, 1 to 4, 2 to 4, 3 to 4, 1 to 3, 2 to 3, or 1 to2. In some embodiments, 5 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.

Independently in some embodiments of 5, and independently in combinationwith any embodiments of any other relevant substituent classes, 5 can bean integer from 1 to 10, 2 to 10, 3 to 10, 4 to 10, 5 to 10, 6 to 10, 7to 10, 8 to 10, 9 to 10, 1 to 9, 2 to 9, 3 to 9, 4 to 9, 5 to 9, 6 to 9,7 to 9, 8 to 9, 1 to 8, 2 to 8, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 7 to 8,1 to 7, 2 to 7, 3 to 7, 4 to 7, 5 to 7, 6 to 7, 1 to 6, 2 to 6, 3 to 6,4 to 6, 5 to 6, 1 to 5, 2 to 5, 3 to 5, 4 to 5, 1 to 4, 2 to 4, 3 to 4,1 to 3, 2 to 3, or 1 to 2. Independently in some embodiments of 5, andindependently in combination with any embodiments of any other relevantsubstituent classes, 5 can be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

Independently in some embodiments of 5, and independently in combinationwith any embodiments of any other relevant substituent classes, 5 can bean integer from 1 to 5, 2 to 5, 3 to 5, 4 to 5, 1 to 4, 2 to 4, 3 to 4,1 to 3, 2 to 3, or 1 to 2. Independently in some embodiments of 5, andindependently in combination with any embodiments of any other relevantsubstituent classes, 5 can be 1, 2, 3, 4, or 5.

Independently in some embodiments of k, and independently in combinationwith any embodiments of any other relevant substituent classes, k can bean integer from 1 to 20, 2 to 20, 3 to 20, 4 to 20, 5 to 20, 6 to 20, 7to 20, 8 to 20, 9 to 20, 10 to 20, 11 to 20, 12 to 20, 13 to 20, 14 to20, 15 to 20, 16 to 20, 17 to 20, 18 to 20, 19 to 20, 1 to 19, 2 to 19,3 to 19, 4 to 19, 5 to 19, 6 to 19, 7 to 19, 8 to 19, 9 to 19, 10 to 19,11 to 19, 12 to 19, 13 to 19, 14 to 19, 15 to 19, 16 to 19, 17 to 19, 18to 19, 1 to 18, 2 to 18, 3 to 18, 4 to 18, to 18, 6 to 18, 7 to 18, 8 to18, 9 to 18, 10 to 18, 11 to 18, 12 to 18, 13 to 18, 14 to 18, to 18, 16to 18, 17 to 18, 1 to 17, 2 to 17, 3 to 17, 4 to 17, 5 to 17, 6 to 17, 7to 17, 8 to 17, 9 to 17, 10 to 17, 11 to 17, 12 to 17, 13 to 17, 14 to17, 15 to 17, 16 to 17, 1 to 16, 2 to 16, 3 to 16, 4 to 16, 5 to 16, 6to 16, 7 to 16, 8 to 16, 9 to 16, 10 to 16, 11 to 16, 12 to 16, 13 to16, 14 to 16, 15 to 16, 1 to 15, 2 to 15, 3 to 15, 4 to 15, 5 to 15, 6to 15, 7 to 15, 8 to 15, 9 to 15, 10 to 15, 11 to 15, 12 to 15, 13 to15, 14 to 15, 1 to 14, 2 to 14, 3 to 14, 4 to 14, 5 to 14, 6 to 14, 7 to14, 8 to 14, 9 to 14, 10 to 14, 11 to 14, 12 to 14, 13 to 14, 1 to 13, 2to 13, 3 to 13, 4 to 13, 5 to 13, 6 to 13, 7 to 13, 8 to 13, 9 to 13, 10to 13, 11 to 13, 12 to 13, 1 to 12, 2 to 12, 3 to 12, 4 to 12, 5 to 12,6 to 12, 7 to 12, 8 to 12, 9 to 12, 10 to 12, 11 to 12, 1 to 11, 2 to11, 3 to 11, 4 to 11, 5 to 11, 6 to 11, 7 to 11, 8 to 11, 9 to 11, 10 to11, 1 to 10, 2 to 10, 3 to 10, 4 to 10, 5 to 10, 6 to 10, 7 to 10, 8 to10, 9 to 10, 1 to 9, 2 to 9, 3 to 9, 4 to 9, 5 to 9, 6 to 9, 7 to 9, 8to 9, 1 to 8, 2 to 8, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 7 to 8, 1 to 7, 2to 7, 3 to 7, 4 to 7, 5 to 7, 6 to 7, 1 to 6, 2 to 6, 3 to 6, 4 to 6, 5to 6, 1 to 5, 2 to 5, 3 to 5, 4 to 5, 1 to 4, 2 to 4, 3 to 4, 1 to 3, 2to 3, or 1 to 2. In some embodiments, k is 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

Independently in some embodiments of k, and independently in combinationwith any embodiments of any other relevant substituent classes, k can bean integer from 1 to 10, 2 to 10, 3 to 10, 4 to 10, 5 to 10, 6 to 10, 7to 10, 8 to 10, 9 to 10, 1 to 9, 2 to 9, 3 to 9, 4 to 9, 5 to 9, 6 to 9,7 to 9, 8 to 9, 1 to 8, 2 to 8, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 7 to 8,1 to 7, 2 to 7, 3 to 7, 4 to 7, 5 to 7, 6 to 7, 1 to 6, 2 to 6, 3 to 6,4 to 6, 5 to 6, 1 to 5, 2 to 5, 3 to 5, 4 to 5, 1 to 4, 2 to 4, 3 to 4,1 to 3, 2 to 3, or 1 to 2. Independently in some embodiments of k, andindependently in combination with any embodiments of any other relevantsubstituent classes, k can be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

Independently in some embodiments of w, and independently in combinationwith any embodiments of any other relevant substituent classes, w can bean integer from 1 to 9, 2 to 9, 3 to 9, 4 to 9, 5 to 9, 6 to 9, 7 to 9,8 to 9, 1 to 8, 2 to 8, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 7 to 8, 1 to 7,2 to 7, 3 to 7, 4 to 7, 5 to 7, 6 to 7, 1 to 6, 2 to 6, 3 to 6, 4 to 6,5 to 6, 1 to 5, 2 to 5, 3 to 5, 4 to 5, 1 to 4, 2 to 4, 3 to 4, 1 to 3,2 to 3, or 1 to 2. Independently in some embodiments of w, andindependently in combination with any embodiments of any other relevantsubstituent classes, w can be 1, 2, 3, 4, 5, 6, 7, 8, or 9.

Independently in some embodiments of w, and independently in combinationwith any embodiments of any other relevant substituent classes, w can bean integer from 1 to 5, 2 to 5, 3 to 5, 4 to 5, 1 to 4, 2 to 4, 3 to 4,1 to 3, 2 to 3, or 1 to 2. In preferred embodiments, w is 1, 2, 3, 4, or5.

Independently in some embodiments of y, and independently in combinationwith any embodiments of any other relevant substituent classes, y can bean integer from 1 to 11, 2 to 11, 3 to 11, 4 to 11, 5 to 11, 6 to 11, 7to 11, 8 to 11, 9 to 11, 10 to 11, 1 to 10, 2 to 10, 3 to 10, 4 to 10, 5to 10, 6 to 10, 7 to 10, 8 to 10, 9 to 10, 1 to 9, 2 to 9, 3 to 9, 4 to9, 5 to 9, 6 to 9, 7 to 9, 8 to 9, 1 to 8, 2 to 8, 3 to 8, 4 to 8, 5 to8, 6 to 8, 7 to 8, 1 to 7, 2 to 7, 3 to 7, 4 to 7, 5 to 7, 6 to 7, 1 to6, 2 to 6, 3 to 6, 4 to 6, 5 to 6, 1 to 5, 2 to 5, 3 to 5, 4 to 5, 1 to4, 2 to 4, 3 to 4, 1 to 3, 2 to 3, or 1 to 2. Independently in someembodiments of y, and independently in combination with any embodimentsof any other relevant substituent classes, y can be 1, 2, 3, 4, 5, 6, 7,8, 9, 10, or 11.

Independently in some embodiments of y, and independently in combinationwith any embodiments of any other relevant substituent classes, y can bean integer from 1 to 5, 2 to 5, 3 to 5, 4 to 5, 1 to 4, 2 to 4, 3 to 4,1 to 3, 2 to 3, or 1 to 2. Independently in some embodiments of y, andindependently in combination with any embodiments of any other relevantsubstituent classes, y can be 1, 2, 3, 4, or 5.

Independently in some embodiments of p and q, and independently incombination with any embodiments of any other relevant substituentclasses, p and q can be, independently, an integer from 1 to 5, 2 to 5,3 to 5, 4 to 5, 1 to 4, 2 to 4, 3 to 4, 1 to 3, 2 to 3, or 1 to 2.Independently in some embodiments of p and q, and independently incombination with any embodiments of any other relevant substituentclasses, p and q can be, independently, 1, 2, 3, 4, or 5.

In some embodiments, modified alginates are alginate polymers thatcontain one or more covalently modified monomers defined by Formula I

In some embodiments, the modified alginate is defined by Formula Ia,Formula Ib, or a combination of Formula Ia and Formula Ib,

wherein, for Formula I, Formula Ia or Formula Ib,

X is oxygen, sulfur, or NR₄;

R₁ is independently in the one or more modified monomers

wherein a is an integer from 1 to 30, z is an integer from 0 to 5, n isan integer from 1 to 12, m is an integer from 3 to 16, and R^(a) andR^(b) are independently selected from U₃, U₃+Q₁; U₃+Q₂, U₃+Q₃, U₃+Q₄,U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃U₃+Q₂+Q₄, U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃,U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄, preferablyU₃+Q₁+Q₂+Q₃; or together with the carbon atom to which they areattached, form a 3- to 8-membered unsubstituted or substitutedcarbocyclic or heterocyclic ring; wherein

Y and Y₂ independently are hydrogen or —PO(OR₅)₂; or

Y₂ is absent, and Y₁. together with the two oxygen atoms to which Y₁ andY₂ are attached form a cyclic structure as shown in Formula II, FormulaIIa, Formula IIb, or a combination of Formula IIa and Formula IIb

wherein, for Formula II, Formula IIa or Formula IIb,

R₂ and R₃ are, independently, hydrogen or an organic grouping containingany number of carbon atoms, 1-30 carbon atoms, 1-20 carbon atoms, or1-14 carbon atoms, and optionally including one or more heteroatoms suchas oxygen, sulfur, or nitrogen grouping in linear, branched, or cyclicstructural formats, representative R₂ and R₃ groupings being thosepresent in U₁; U₁+Q₁; U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄,U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄,U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃: or

R₂ and R₃, together with the carbon atom to which they are attached,form a 3- to 8-membered unsubstituted or substituted carbocyclic orheterocyclic ring; and

R₄, R₅, R₆, R₈, and R₉ are, independently, hydrogen or an organicgrouping containing any number of carbon atoms, 1-30 carbon atoms, 1-20carbon atoms, or 1-14 carbon atoms, and optionally including one or moreheteroatoms such as oxygen, sulfur, or nitrogen grouping in linear,branched, or cyclic structural formats, representative organic groupingsbeing those present in U₁; U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂,U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃,U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferablyU₁+Q₁+Q₃.

Independently in some embodiments of a, and independently in combinationwith any embodiments of any other relevant substituent classes, a can bean integer from 1 to 30, 2 to 30, 3 to 30, 4 to 30, 5 to 30, 6 to 30, 7to 30, 8 to 30, 9 to 30, 10 to 30, 11 to 30, 12 to 30, 13 to 30, 14 to30, 15 to 30, 16 to 30, 17 to 30, 18 to 30, 19 to 30, 20 to 30, 21 to30, 22 to 30, 23 to 30, 24 to 30, 25 to 30, 26 to 30, 27 to 30, 28 to30, 29 to 30, 1 to 29, 2 to 29, 3 to 29, 4 to 29, 5 to 29, 6 to 29, 7 to29, 8 to 29, 9 to 29, 10 to 29, 11 to 29, 12 to 29, 13 to 29, 14 to 29,15 to 29, 16 to 29, 17 to 29, 18 to 29, 19 to 29, 20 to 29, 21 to 29, 22to 29, 23 to 29, 24 to 29, 25 to 29, 26 to 29, 27 to 29, 28 to 29, 1 to28, 2 to 28, 3 to 28, 4 to 28, 5 to 28, 6 to 28, 7 to 28, 8 to 28, 9 to28, 10 to 28, 11 to 28, 12 to 28, 13 to 28, 14 to 28, 15 to 28, 16 to28, 17 to 28, 18 to 28, 19 to 28, 20 to 28, 21 to 28, 22 to 28, 23 to28, 24 to 28, 25 to 28, 26 to 28, 27 to 28, 1 to 27, 2 to 27, 3 to 27, 4to 27, 5 to 27, 6 to 27, 7 to 27, 8 to 27, 9 to 27, 10 to 27, 11 to 27,12 to 27, 13 to 27, 14 to 27, 15 to 27, 16 to 27, 17 to 27, 18 to 27, 19to 27, 20 to 27, 21 to 27, 22 to 27, 23 to 27, 24 to 27, 25 to 27, 26 to27, 1 to 26, 2 to 26, 3 to 26, 4 to 26, 5 to 26, 6 to 26, 7 to 26, 8 to26, 9 to 26, to 26, 11 to 26, 12 to 26, 13 to 26, 14 to 26, 15 to 26, 16to 26, 17 to 26, 18 to 26, 19 to 26, 20 to 26, 21 to 26, 22 to 26, 23 to26, 24 to 26, 25 to 26, 1 to 25, 2 to 25, 3 to 25, 4 to 25, 5 to 25, 6to 25, 7 to 25, 8 to 25, 9 to 25, 10 to 25, 11 to 25, 12 to 25, 13 to25, 14 to 25, 15 to 25, 16 to 25, 17 to 25, 18 to 25, 19 to 25, 20 to25, 21 to 25, 22 to 25, 23 to 25, 24 to 25, 1 to 24, 2 to 24, 3 to 24, 4to 24, 5 to 24, 6 to 24, 7 to 24, 8 to 24, 9 to 24, 10 to 24, 11 to 24,12 to 24, 13 to 24, 14 to 24, 15 to 24, 16 to 24, 17 to 24, 18 to 24, 19to 24, 20 to 24, 21 to 24, 22 to 24, 23 to 24, 1 to 23, 2 to 23, 3 to23, 4 to 23, 5 to 23, 6 to 23, 7 to 23, 8 to 23, 9 to 23, 10 to 23, 11to 23, 12 to 23, 13 to 23, 14 to 23, 15 to 23, 16 to 23, 17 to 23, 18 to23, 19 to 23, 20 to 23, 21 to 23, 22 to 23, 1 to 22, 2 to 22, 3 to 22, 4to 22, 5 to 22, 6 to 22, 7 to 22, 8 to 22, 9 to 22, 10 to 22, 11 to 22,12 to 22, 13 to 22, 14 to 22, 15 to 22, 16 to 22, 17 to 22, 18 to 22, 19to 22, 20 to 22, 21 to 22, 1 to 21, 2 to 21, 3 to 21, 4 to 21, 5 to 21,6 to 21, 7 to 21, 8 to 21, 9 to 21, 10 to 21, 11 to 21, 12 to 21, 13 to21, 14 to 21, 15 to 21, 16 to 21, 17 to 21, 18 to 21, 19 to 21, 20 to21, 1 to 20, 2 to 20, 3 to 20, 4 to 20, 5 to 20, 6 to 20, 7 to 20, 8 to20, 9 to 20, 10 to 20, 11 to 20, 12 to 20, 13 to 20, 14 to 20, 15 to 20,16 to 20, 17 to 20, 18 to 20, 19 to 20, 1 to 19, 2 to 19, 3 to 19, 4 to19, 5 to 19, 6 to 19, 7 to 19, 8 to 19, 9 to 19, 10 to 19, 11 to 19, 12to 19, 13 to 19, 14 to 19, 15 to 19, 16 to 19, 17 to 19, 18 to 19, 1 to18, 2 to 18, 3 to 18, 4 to 18, 5 to 18, 6 to 18, 7 to 18, 8 to 18, 9 to18, 10 to 18, 11 to 18, 12 to 18, 13 to 18, 14 to 18, 15 to 18, 16 to18, 17 to 18, 1 to 17, 2 to 17, 3 to 17, 4 to 17, 5 to 17, 6 to 17, 7 to17, 8 to 17, 9 to 17, to 17, 11 to 17, 12 to 17, 13 to 17, 14 to 17, 15to 17, 16 to 17, 1 to 16, 2 to 16, 3 to 16, 4 to 16, 5 to 16, 6 to 16, 7to 16, 8 to 16, 9 to 16, 10 to 16, 11 to 16, 12 to 16, 13 to 16, 14 to16, 15 to 16, 1 to 15, 2 to 15, 3 to 15, 4 to 15, 5 to 15, 6 to 15, 7 to15, 8 to 15, 9 to 15, 10 to 15, 11 to 15, 12 to 15, 13 to 15, 14 to 15,1 to 14, 2 to 14, 3 to 14, 4 to 14, 5 to 14, 6 to 14, 7 to 14, 8 to 14,9 to 14, 10 to 14, 11 to 14, 12 to 14, 13 to 14, 1 to 13, 2 to 13, 3 to13, 4 to 13, 5 to 13, 6 to 13, 7 to 13, 8 to 13, 9 to 13, 10 to 13, 11to 13, 12 to 13, 1 to 12, 2 to 12, 3 to 12, 4 to 12, 5 to 12, 6 to 12, 7to 12, 8 to 12, 9 to 12, 10 to 12, 11 to 12, 1 to 11, 2 to 11, 3 to 11,4 to 11, 5 to 11, 6 to 11, 7 to 11, 8 to 11, 9 to 11, 10 to 11, 1 to 10,2 to 10, 3 to 10, 4 to 10, 5 to 10, 6 to 10, 7 to 10, 8 to 10, 9 to 10,1 to 9, 2 to 9, 3 to 9, 4 to 9, 5 to 9, 6 to 9, 7 to 9, 8 to 9, 1 to 8,2 to 8, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 7 to 8, 1 to 7, 2 to 7, 3 to 7,4 to 7, 5 to 7, 6 to 7, 1 to 6, 2 to 6, 3 to 6, 4 to 6, 5 to 6, 1 to 5,2 to 5, 3 to 5, 4 to 5, 1 to 4, 2 to 4, 3 to 4, 1 to 3, 2 to 3, or 1 to2. In some embodiments, a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.

Independently in some embodiments of a, and independently in combinationwith any embodiments of any other relevant substituent classes, a can bean integer from 1 to 10, 2 to 10, 3 to 10, 4 to 10, 5 to 10, 6 to 10, 7to 10, 8 to 10, 9 to 10, 1 to 9, 2 to 9, 3 to 9, 4 to 9, 5 to 9, 6 to 9,7 to 9, 8 to 9, 1 to 8, 2 to 8, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 7 to 8,1 to 7, 2 to 7, 3 to 7, 4 to 7, 5 to 7, 6 to 7, 1 to 6, 2 to 6, 3 to 6,4 to 6, 5 to 6, 1 to 5, 2 to 5, 3 to 5, 4 to 5, 1 to 4, 2 to 4, 3 to 4,1 to 3, 2 to 3, or 1 to 2. Independently in some embodiments of a, andindependently in combination with any embodiments of any other relevantsubstituent classes, a can be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

Independently in some embodiments of a, and independently in combinationwith any embodiments of any other relevant substituent classes, a can bean integer from 1 to 5, 2 to 5, 3 to 5, 4 to 5, 1 to 4, 2 to 4, 3 to 4,1 to 3, 2 to 3, or 1 to 2. In preferred embodiments, a is 1, 2, 3, 4, or5.

Independently in some embodiments of m, and independently in combinationwith any embodiments of any other relevant substituent classes, m can bean integer from 3 to 16, 4 to 16, 5 to 16, 6 to 16, 7 to 16, 8 to 16, 9to 16, 10 to 16, 11 to 16, 12 to 16, 13 to 16, 14 to 16, 15 to 16, 3 to15, 4 to 15, 5 to 15, 6 to 15, 7 to 15, 8 to 15, 9 to 15, 10 to 15, 11to 15, 12 to 15, 13 to 15, 14 to 15, 3 to 14, 4 to 14, 5 to 14, 6 to 14,7 to 14, 8 to 14, 9 to 14, 10 to 14, 11 to 14, 12 to 14, 13 to 14, 3 to13, 4 to 13, 5 to 13, 6 to 13, 7 to 13, 8 to 13, 9 to 13, 10 to 13, 11to 13, 12 to 13, 3 to 12, 4 to 12, 5 to 12, 6 to 12, 7 to 12, 8 to 12, 9to 12, 10 to 12, 11 to 12, 3 to 11, 4 to 11, 5 to 11, 6 to 11, 7 to 11,8 to 11, 9 to 11, 10 to 11, 3 to 10, 4 to 10, 5 to 10, 6 to 10, 7 to 10,8 to 10, 9 to 10, 3 to 9, 4 to 9, 5 to 9, 6 to 9, 7 to 9, 8 to 9, 3 to8, 4 to 8, 5 to 8, 6 to 8, 7 to 8, 3 to 7, 4 to 7, 5 to 7, 6 to 7, 3 to6, 4 to 6, 5 to 6, 3 to 5, 4 to 5, and 3 to 4. In some embodiments, m is3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

Independently in some embodiments of m, and independently in combinationwith any embodiments of any other relevant substituent classes, m can bean integer from 3 to 10, 4 to 10, 5 to 10, 6 to 10, 7 to 10, 8 to 10, 9to 10, 3 to 9, 4 to 9, 5 to 9, 6 to 9, 7 to 9, 8 to 9, 3 to 8, 4 to 8, 5to 8, 6 to 8, 7 to 8, 3 to 7, 4 to 7, 5 to 7, 6 to 7, 3 to 6, 4 to 6, 5to 6, 3 to 5, 4 to 5, and 3 to 4. Independently in some embodiments ofm, and independently in combination with any embodiments of any otherrelevant substituent classes, m can be 3, 4, 5, 6, 7, 8, 9, or 10.

Independently in some embodiments of m, and independently in combinationwith any embodiments of any other relevant substituent classes, m can bean integer from 3 to 5, 4 to 5, or 3 to 4. In preferred embodiments, mis 3, 4, or 5.

Independently in some embodiments of n, and independently in combinationwith any embodiments of any other relevant substituent classes, n can bean integer from 1 to 12, 2 to 12, 3 to 12, 4 to 12, 5 to 12, 6 to 12, 7to 12, 8 to 12, 9 to 12, 10 to 12, 11 to 12, 1 to 11, 2 to 11, 3 to 11,4 to 11, 5 to 11, 6 to 11, 7 to 11, 8 to 11, 9 to 11, 10 to 11, 1 to 10,2 to 10, 3 to 10, 4 to 10, 5 to 10, 6 to 10, 7 to 10, 8 to 10, 9 to 10,1 to 9, 2 to 9, 3 to 9, 4 to 9, 5 to 9, 6 to 9, 7 to 9, 8 to 9, 1 to 8,2 to 8, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 7 to 8, 1 to 7, 2 to 7, 3 to 7,4 to 7, 5 to 7, 6 to 7, 1 to 6, 2 to 6, 3 to 6, 4 to 6, 5 to 6, 1 to 5,2 to 5, 3 to 5, 4 to 5, 1 to 4, 2 to 4, 3 to 4, 1 to 3, 2 to 3, or 1 to2. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, or 20.

Independently in some embodiments of n, and independently in combinationwith any embodiments of any other relevant substituent classes, n can bean integer from 1 to 5, 2 to 5, 3 to 5, 4 to 5, 1 to 4, 2 to 4, 3 to 4,1 to 3, 2 to 3, or 1 to 2. In preferred embodiments, n is 1, 2, 3, 4, or5.

In some embodiments, modified alginates are alginate polymers thatcontain one or more covalently modified monomers defined by Formula I

In some embodiments, the modified alginate is defined by Formula Ia orFormula Ib

wherein, for Formula I, Formula Ia or Formula Ib,

X is oxygen, sulfur, or NR₄;

R₁ is, independently in the one or more modified monomers,

wherein k is an integer from 1 to 10; wherein z is an integer from 0 to5; wherein w is an integer from 0 to 4; wherein X₄ is absent, O or S;

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₁, R₃₉, R₄₀, and R₄₁ areindependently hydrogen, U₁, U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂,U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃,U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferablyU₁+Q₁+Q₂+Q₃;

wherein R₃₇ is C or Si;

wherein X_(g) and R₃₈ are independently U₁; U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄,U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃,U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferablyU₁+Q₁+Q₂+Q₃+Q₄; and

wherein R^(a) and R^(c) are independently U₃, U₃+Q₁, U₃+Q₂, U₃+Q₃,U₃+Q₄, U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄,U₃+Q₁+Q₂+Q₃, U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄,preferably U₃+Q₁+Q₃; or together with the carbon atom to which they areattached, form a 3- to 8-membered unsubstituted or substitutedcarbocyclic, heterocyclic ring or

wherein R₈, R₉, or both are, independently, hydrogen, alkyl, substitutedalkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, alkenyl,alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl,carbonyl, substituted carbonyl, carbinol,

wherein R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are, independently, hydrogen,U. U₁+Q₁; U₁+Q₂, U₁+Q₃, U₁+Q₄, U₄+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₄+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃;

wherein R₃₁, R₃₄, R₃₅, and R₃₆ are independently present or absentaccording to valency, and wherein the ring bonds are double or singleaccording to valency;

wherein in R_(x) or R₉:

y is an integer from 0 to 11;

R^(e) are each independently U₃, U₃+Q₁; U₃+Q₂, U₃+Q₃, U₃+Q₄, U₃+Q₂+Q₂,U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃,U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄, preferablyU₃+Q₁+Q₃; or together with the carbon atom to which they are attached,form a 3- to 8-membered unsubstituted or substituted carbocyclic orheterocyclic ring;

R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are independently C, O, N, or S,wherein the bonds between adjacent R₁₈ to R₂₃ are double or singleaccording to valency, and wherein R₁₈ to R₂₃ are bound to none, one, ortwo hydrogens according to valency; and R₂₄ is independently—(CR₂₅R₂₅)_(p)— or —(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and qare independently integers from 0 to 5, wherein X_(b) is absent, —O—,—S—, —SO₂-, or NR₄, wherein each R₂₅ is, as valency permits,independently absent, hydrogen, =O, ═S, —OH, -SH, —NR₄, wherein R₄ is 1%U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃:

wherein R₈, and R₉ are not both hydrogen; wherein at least one R^(b) orR^(c) is defined by Formula XIII;

wherein

Y₁ and Y₂ independently are hydrogen or —PO(OR₅)₂; or

Y₂ is absent, and Y₁. together with the two oxygen atoms to which Y₁ andY₂ are attached form a cyclic structure as shown in Formula II, FormulaIIa, Formula IIb, or a combination of Formula IIa and Formula IIb

wherein, for Formula II, Formula IIa or Formula IIb,

R₂ and R₃ are, independently, hydrogen or an organic grouping containingany number of carbon atoms, 1-30 carbon atoms, 1-20 carbon atoms, or1-14 carbon atoms, and optionally including one or more heteroatoms suchas oxygen, sulfur, or nitrogen grouping in linear, branched, or cyclicstructural formats, representative R₂ and R₃ groupings being thosepresent in U₁; U₁+Q₁; U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄,U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄,U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃: or

R₂ and R₃, together with the carbon atom to which they are attached,form a 3- to 8-membered unsubstituted or substituted carbocyclic orheterocyclic ring; and

R₄ and R₅ are, independently, hydrogen or an organic grouping containingany number of carbon atoms, 1-30 carbon atoms, 1-20 carbon atoms, or1-14 carbon atoms, and optionally including one or more heteroatoms suchas oxygen, sulfur, or nitrogen grouping in linear, branched, or cyclicstructural formats, representative organic groupings being those presentin U₁; U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄,U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄,U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of R₈ and R₉, and independently incombination with any embodiments of any other relevant substituentclasses, R₈ and R₉ can be, independently,

wherein k is an integer from 1 to 20;

wherein X₄ are O;

wherein R^(c) is R^(b), absent, hydrogen, U₃, U₃+Q₁, U₃+Q₂, U₃+Q₃,U₃+Q₄, U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄,U₃+Q₁+Q₂+Q₃, U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₄+Q₂+Q₃+Q₄,preferably U₃+Q₄+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independentlyR^(b), hydrogen, U₁, U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃,U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄,U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, all of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are C. Independently insome embodiments of Formula IX, and independently in combination withany embodiments of any other relevant substituent classes, one, two,three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are C.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃are C. Independently in some embodiments of Formula IX, andindependently in combination with any embodiments of any other relevantsubstituent classes, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, andR₂₃ are C. Independently in some embodiments of Formula IX, andindependently in combination with any embodiments of any other relevantsubstituent classes, one or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ areC. Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is C.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, all of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are C. Independently in someembodiments of Formula XIV, and independently in combination with anyembodiments of any other relevant substituent classes, one, two, three,or four of R₁₈, R₁₉, R₂₀, R₂₁; and R₂₂ are C. Independently in someembodiments of Formula XIV, and independently in combination with anyembodiments of any other relevant substituent classes, one, two, orthree of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are C. Independently in someembodiments of Formula XIV, and independently in combination with anyembodiments of any other relevant substituent classes, one or two ofR₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are C. Independently in some embodiments ofFormula XIV, and independently in combination with any embodiments ofany other relevant substituent classes, one of R₁₈, R₁₉, R₂₀, R₂₁, andR₂₂ is C.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, all of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are N. Independently insome embodiments of Formula IX, and independently in combination withany embodiments of any other relevant substituent classes, one, two,three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are N.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃are N. Independently in some embodiments of Formula IX, andindependently in combination with any embodiments of any other relevantsubstituent classes, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, andR₂₃ are N. Independently in some embodiments of Formula IX, andindependently in combination with any embodiments of any other relevantsubstituent classes, one or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ areN. Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is N.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, all of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are N. Independently in someembodiments of Formula XIV, and independently in combination with anyembodiments of any other relevant substituent classes, one, two, three,or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are N. Independently in someembodiments of Formula XIV, and independently in combination with anyembodiments of any other relevant substituent classes, one, two, orthree of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are N. Independently in someembodiments of Formula XIV, and independently in combination with anyembodiments of any other relevant substituent classes, one or two ofR₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are N. Independently in some embodiments ofFormula XIV, and independently in combination with any embodiments ofany other relevant substituent classes, one of R₁₈, R₁₉, R₂₀, R₂₁, andR₂₂ is N.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, all of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are O. Independently insome embodiments of Formula IX, and independently in combination withany embodiments of any other relevant substituent classes, one, two,three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are O.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃are O. Independently in some embodiments of Formula IX, andindependently in combination with any embodiments of any other relevantsubstituent classes, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, andR₂₃ are O. Independently in some embodiments of Formula IX, andindependently in combination with any embodiments of any other relevantsubstituent classes, one or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ areO. Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is O.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, all of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are O. Independently in someembodiments of Formula XIV, and independently in combination with anyembodiments of any other relevant substituent classes, one, two, three,or four of R₁₈, R₁₉, R₂₀, R₂₁; and R₂₂ are O. Independently in someembodiments of Formula XIV, and independently in combination with anyembodiments of any other relevant substituent classes, one, two, orthree of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are O. Independently in someembodiments of Formula XIV, and independently in combination with anyembodiments of any other relevant substituent classes, one or two ofR₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are O. Independently in some embodiments ofFormula XIV, and independently in combination with any embodiments ofany other relevant substituent classes, one of R₁₈, R₁₉, R₂₀, R₂₁, andR₂₂ is O.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, all of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S. Independently insome embodiments of Formula IX, and independently in combination withany embodiments of any other relevant substituent classes, one, two,three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃are S. Independently in some embodiments of Formula IX, andindependently in combination with any embodiments of any other relevantsubstituent classes, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, andR₂₃ are S. Independently in some embodiments of Formula IX, andindependently in combination with any embodiments of any other relevantsubstituent classes, one or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ areS. Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, all of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S. Independently in someembodiments of Formula XIV, and independently in combination with anyembodiments of any other relevant substituent classes, one, two, three,or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S. Independently in someembodiments of Formula XIV, and independently in combination with anyembodiments of any other relevant substituent classes, one, two, orthree of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S. Independently in someembodiments of Formula XIV, and independently in combination with anyembodiments of any other relevant substituent classes, one or two ofR₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S. Independently in some embodiments ofFormula XIV, and independently in combination with any embodiments ofany other relevant substituent classes, one of R₁₈, R₁₉, R₂₀, R₂₁, andR₂₂ is S.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, all of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S(O)₂.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, andR₂₃ are S(O)₂. Independently in some embodiments of Formula IX, andindependently in combination with any embodiments of any other relevantsubstituent classes, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are S(O)₂. Independently in some embodiments of Formula IX,and independently in combination with any embodiments of any otherrelevant substituent classes, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are S(O)₂. Independently in some embodiments of Formula IX,and independently in combination with any embodiments of any otherrelevant substituent classes, one or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, andR₂₃ are S(O)2. Independently in some embodiments of Formula IX, andindependently in combination with any embodiments of any other relevantsubstituent classes, one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S(O)₂.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, all of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S(O)₂. Independently insome embodiments of Formula XIV, and independently in combination withany embodiments of any other relevant substituent classes, one, two,three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S(O)₂. Independentlyin some embodiments of Formula XIV, and independently in combinationwith any embodiments of any other relevant substituent classes, one,two, or three of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S(O)₂. Independently insome embodiments of Formula XIV, and independently in combination withany embodiments of any other relevant substituent classes, one or two ofR₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S(O)₂. Independently in some embodimentsof Formula XIV, and independently in combination with any embodiments ofany other relevant substituent classes, one of R₁₈, Rw, R₂₀, R₂₁, andR₂₂ is S(O)₂.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, andR₂₃ are N and one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is O.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃are N and one or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are O.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are Nand one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are O.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are N and one,two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are O.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is N and one, two,three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are O.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are Nand one of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is O. Independently in someembodiments of Formula XIV, and independently in combination with anyembodiments of any other relevant substituent classes, one, two, orthree of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are N and one or two of R₁₈, R₁₉,R₂₀, R₂₁, and R₂₂ are O. Independently in some embodiments of FormulaXIV, and independently in combination with any embodiments of any otherrelevant substituent classes, one or two of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂are N and one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are O.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is N and one, two, three, orfour of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are O.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, andR₂₃ are N and one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃are N and one or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are Nand one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are N and one,two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is N and one, two,three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are Nand one of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is S. Independently in someembodiments of Formula XIV, and independently in combination with anyembodiments of any other relevant substituent classes, one, two, orthree of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are N and one or two of R₁₈, R₁₉,R₂₀, R₂₁, and R₂₂ are S. Independently in some embodiments of FormulaXIV, and independently in combination with any embodiments of any otherrelevant substituent classes, one or two of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂are N and one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is N and one, two, three, orfour of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, andR₂₃ are N and one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S(O)₂.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃are N and one or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S(O)₂.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are Nand one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S(O)2.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are N and one,two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S(O)₂.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is N and one, two,three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S(O)₂.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are Nand one of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is S(O)₂. Independently in someembodiments of Formula XIV, and independently in combination with anyembodiments of any other relevant substituent classes, one, two, orthree of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are N and one or two of R₁₈, R₁₉,R₂₀, R₂₁, and R₂₂ are S(O)₂. Independently in some embodiments ofFormula XIV, and independently in combination with any embodiments ofany other relevant substituent classes, one or two of R₁₈, R₁₉, R₂₀,R₂₁, and R₂₂ are N and one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂are S(O)₂. Independently in some embodiments of Formula XIV, andindependently in combination with any embodiments of any other relevantsubstituent classes, one of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is N and one,two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S(O)₂.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, andR₂₃ are O and one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃are O and one or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are Oand one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are O and one,two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is N and one, two,three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are Oand one of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is S. Independently in someembodiments of Formula XIV, and independently in combination with anyembodiments of any other relevant substituent classes, one, two, orthree of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are O and one or two of R₁₈, R₁₉,R₂₀, R₂₁, and R₂₂ are S. Independently in some embodiments of FormulaXIV, and independently in combination with any embodiments of any otherrelevant substituent classes, one or two of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂are O and one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is O and one, two, three, orfour of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, andR₂₃ are O and one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S(O)₂.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃are O and one or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S(O)₂.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are Oand one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S(O)₂.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are O and one,two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S(O)₂.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is O and one, two,three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S(O)₂.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are Oand one of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is S(O)₂. Independently in someembodiments of Formula XIV, and independently in combination with anyembodiments of any other relevant substituent classes, one, two, orthree of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are O and one or two of R₁₈, R₁₉,R₂₀, R₂₁, and R₂₂ are S(O)₂. Independently in some embodiments ofFormula XIV, and independently in combination with any embodiments ofany other relevant substituent classes, one or two of R₁₈, R₁₉, R₂₀,R₂₁, and R₂₂ are O and one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂are S(O)₂. Independently in some embodiments of Formula XIV, andindependently in combination with any embodiments of any other relevantsubstituent classes, one of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is O and one,two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S(O)₂.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, andR₂₃ are S and one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S(O)₂.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃are S and one or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S(O)₂.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are Sand one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S(O)₂.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S and one,two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S(O)₂.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S and one, two,three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S(O)₂.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are Sand one of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is S(O)₂. Independently in someembodiments of Formula XIV, and independently in combination with anyembodiments of any other relevant substituent classes, one, two, orthree of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S and one or two of R₁₈, R₁₉,R₂₀, R₂₁, and R₂₂ are S(O)₂. Independently in some embodiments ofFormula XIV, and independently in combination with any embodiments ofany other relevant substituent classes, one or two of R₁₈, R₁₉, R₂₀,R₂₁, and R₂₂ are S and one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂are S(O)₂. Independently in some embodiments of Formula XIV, andindependently in combination with any embodiments of any other relevantsubstituent classes, one of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is S and one,two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S(O)₂.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, andR₂₃ are N and the others are C. Independently in some embodiments ofFormula IX, and independently in combination with any embodiments of anyother relevant substituent classes, one, two, three, or four of R₁₈,R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are N and the others are C. Independently insome embodiments of Formula IX, and independently in combination withany embodiments of any other relevant substituent classes, one, two, orthree of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are N and the others are C.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are N and theothers are C. Independently in some embodiments of Formula IX, andindependently in combination with any embodiments of any other relevantsubstituent classes, one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is N andthe others are C.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are Nand the others are C. Independently in some embodiments of Formula XIV,and independently in combination with any embodiments of any otherrelevant substituent classes, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁,and R₂₂ are N and the others are C. Independently in some embodiments ofFormula XIV, and independently in combination with any embodiments ofany other relevant substituent classes, one or two of R₁₈, R₁₉, R₂₀,R₂₁, and R₂₂ are N and the others are C. Independently in someembodiments of Formula XIV, and independently in combination with anyembodiments of any other relevant substituent classes, one of R₁₈, R₁₉,R₂₀, R₂₁, and R₂₂ is N and the others are C.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, andR₂₃ are O and the others are C. Independently in some embodiments ofFormula IX, and independently in combination with any embodiments of anyother relevant substituent classes, one, two, three, or four of R₁₈,R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are O and the others are C. Independently insome embodiments of Formula IX, and independently in combination withany embodiments of any other relevant substituent classes, one, two, orthree of R₁₈, R₁₀, R₂₀, R₂₁, R₂₂, and R₂₃ are O and the others are C.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one or two of R₁₈, R₁₀, R₂₀, R₂₁, R₂₂, and R₂₃ are O and theothers are C. Independently in some embodiments of Formula IX, andindependently in combination with any embodiments of any other relevantsubstituent classes, one of R₁₈, R₁₀, R₂₀, R₂₁, R₂₂, and R₂₃ is O andthe others are C.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, or four of R₁₈, R₁₀, R₂₀, R₂₁, and R₂₂ are Oand the others are C. Independently in some embodiments of Formula XIV,and independently in combination with any embodiments of any otherrelevant substituent classes, one, two, or three of R₁₈, R₁₀, R₂₀, R₂₁,and R₂₂ are O and the others are C. Independently in some embodiments ofFormula XIV, and independently in combination with any embodiments ofany other relevant substituent classes, one or two of R₁₈, R₁₀, R₂₀,R₂₁, and R₂₂ are O and the others are C. Independently in someembodiments of Formula XIV, and independently in combination with anyembodiments of any other relevant substituent classes, one of R₁₈, R₁₀,R₂₀, R₂₁, and R₂₂ is O and the others are C.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, four, or five of R₁₈, R₁₀, R₂₀, R₂₁, R₂₂, andR₂₃ are S and the others are C. Independently in some embodiments ofFormula IX, and independently in combination with any embodiments of anyother relevant substituent classes, one, two, three, or four of R₁₈,R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S and the others are C. Independently insome embodiments of Formula IX, and independently in combination withany embodiments of any other relevant substituent classes, one, two, orthree of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S and the others are C.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S and theothers are C. Independently in some embodiments of Formula IX, andindependently in combination with any embodiments of any other relevantsubstituent classes, one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S andthe others are C.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are Sand the others are C. Independently in some embodiments of Formula XIV,and independently in combination with any embodiments of any otherrelevant substituent classes, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁,and R₂₂ are S and the others are C. Independently in some embodiments ofFormula XIV, and independently in combination with any embodiments ofany other relevant substituent classes, one or two of R₁₈, R₁₉, R₂₀,R₂₁, and R₂₂ are S and the others are C. Independently in someembodiments of Formula XIV, and independently in combination with anyembodiments of any other relevant substituent classes, one of R₁₈, R₁₉,R₂₀, R₂₁, and R₂₂ is S and the others are C. Independently in someembodiments of Formula IX, and independently in combination with anyembodiments of any other relevant substituent classes, one, two, three,four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S(O)₂ and theothers are C.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃are S(O)₂ and the others are C. Independently in some embodiments ofFormula IX, and independently in combination with any embodiments of anyother relevant substituent classes, one, two, or three of R₁₈, R₁₉, R₂₀,R₂₁, R₂₂, and R₂₃ are S(O)2 and the others are C. Independently in someembodiments of Formula IX, and independently in combination with anyembodiments of any other relevant substituent classes, one or two ofR₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S(O)₂ and the others are C.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S(O)₂ and the othersare C.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ areS(O)₂ and the others are C. Independently in some embodiments of FormulaXIV, and independently in combination with any embodiments of any otherrelevant substituent classes, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁,and R₂₂ are S(O)₂ and the others are C. Independently in someembodiments of Formula XIV, and independently in combination with anyembodiments of any other relevant substituent classes, one or two ofR₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S(O)₂ and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is S(O)₂ and the others areC.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, four, five, or six of R₁₈, R₁₉, R₂₀,R₂₁, R₂₂, and R₂₃ are N, none, one, two, three, four, five, or six ofR₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is O, and the others are C.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are N, none, one, two, three, four, or five of R₁₈, R₁₉,R₂₀, R₂₁, R₂₂, and R₂₃ is O, and the others are C. Independently in someembodiments of Formula IX, and independently in combination with anyembodiments of any other relevant substituent classes, none, one, two,three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are N, none, one,two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is O, and theothers are C. Independently in some embodiments of Formula IX, andindependently in combination with any embodiments of any other relevantsubstituent classes, none, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are N, none, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,and R₂₃ is O, and the others are C. Independently in some embodiments ofFormula IX, and independently in combination with any embodiments of anyother relevant substituent classes, none, one, or two of R₁₈, R₁₉, R₂₀,R₂₁, R₂₂, and R₂₃ are N, none, one, or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,and R₂₃ is O, and the others are C. Independently in some embodiments ofFormula IX, and independently in combination with any embodiments of anyother relevant substituent classes, none or one of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are N, none or one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ isO, and the others are C.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, andR₂₂ are N, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁,and R₂₂ is O, and the others are C. Independently in some embodiments ofFormula XIV, and independently in combination with any embodiments ofany other relevant substituent classes, none, one, two, three, or fourof R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are N, none, one, two, three, or four ofR₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is O, and the others are C. Independently insome embodiments of Formula XIV, and independently in combination withany embodiments of any other relevant substituent classes, none, one,two, or three of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are N, none, one, two, orthree of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are O, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, none, one or two of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are N, none,one or two of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are O, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, none or one of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is N, none or one ofR₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are O, and the others are C.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, andR₂₃ are N, one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is O, and the othersare C. Independently in some embodiments of Formula IX, andindependently in combination with any embodiments of any other relevantsubstituent classes, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are N, one or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ areO, and the others are C. Independently in some embodiments of FormulaIX, and independently in combination with any embodiments of any otherrelevant substituent classes, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are N, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, andR₂₃ are O, and the others are C. Independently in some embodiments ofFormula IX, and independently in combination with any embodiments of anyother relevant substituent classes, one or two of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are N, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,and R₂₃ are O, and the others are C. Independently in some embodimentsof Formula IX, and independently in combination with any embodiments ofany other relevant substituent classes, one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,and R₂₃ is N, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,and R₂₃ are O, and the others are C.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are N,one of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is O, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are N, one ortwo of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are O, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one or two of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are N, one, two, orthree of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are O, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is N, one, two, three, orfour of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are O, and the others are C.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, four, five, or six of R₁₈, R₁₉, R₂₀,R₂₁, R₂₂, and R₂₃ are N, none, one, two, three, four, five, or six ofR₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S, and the others are C.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are N, none, one, two, three, four, or five of R₁₈, R₁₉,R₂₀, R₂₁, R₂₂, and R₂₃ is S, and the others are C. Independently in someembodiments of Formula IX, and independently in combination with anyembodiments of any other relevant substituent classes, none, one, two,three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are N, none, one,two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S, and theothers are C. Independently in some embodiments of Formula IX, andindependently in combination with any embodiments of any other relevantsubstituent classes, none, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are N, none, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,and R₂₃ is S, and the others are C. Independently in some embodiments ofFormula IX, and independently in combination with any embodiments of anyother relevant substituent classes, none, one, or two of R₁₈, R₁₉, R₂₀,R₂₁, R₂₂, and R₂₃ are N, none, one, or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,and R₂₃ is S, and the others are C. Independently in some embodiments ofFormula IX, and independently in combination with any embodiments of anyother relevant substituent classes, none or one of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are N, none or one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ isS, and the others are C.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, andR₂₂ are N, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁,and R₂₂ is S, and the others are C. Independently in some embodiments ofFormula XIV, and independently in combination with any embodiments ofany other relevant substituent classes, none, one, two, three, or fourof R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are N, none, one, two, three, or four ofR₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is S, and the others are C. Independently insome embodiments of Formula XIV, and independently in combination withany embodiments of any other relevant substituent classes, none, one,two, or three of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are N, none, one, two, orthree of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, none, one or two of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are N, none,one or two of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, none or one of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is N, none or one ofR₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S, and the others are C.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, andR₂₃ are N, one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S, and the othersare C. Independently in some embodiments of Formula IX, andindependently in combination with any embodiments of any other relevantsubstituent classes, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are N, one or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ areS, and the others are C. Independently in some embodiments of FormulaIX, and independently in combination with any embodiments of any otherrelevant substituent classes, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are N, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, andR₂₃ are S, and the others are C. Independently in some embodiments ofFormula IX, and independently in combination with any embodiments of anyother relevant substituent classes, one or two of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are N, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,and R₂₃ are S, and the others are C. Independently in some embodimentsof Formula IX, and independently in combination with any embodiments ofany other relevant substituent classes, one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,and R₂₃ is N, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,and R₂₃ are S, and the others are C.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are N,one of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is S, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are N, one ortwo of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one or two of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are N, one, two, orthree of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is N, one, two, three, orfour of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S, and the others are C.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, four, five, or six of R₁₈, R₁₉, R₂₀,R₂₁, R₂₂, and R₂₃ are N, none, one, two, three, four, five, or six ofR₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S(O)₂, and the others are C.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are N, none, one, two, three, four, or five of R₁₈, R₁₉,R₂₀, R₂₁, R₂₂, and R₂₃ is S(O)₂, and the others are C. Independently insome embodiments of Formula IX, and independently in combination withany embodiments of any other relevant substituent classes, none, one,two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are N, none,one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S(O)₂,and the others are C. Independently in some embodiments of Formula IX,and independently in combination with any embodiments of any otherrelevant substituent classes, none, one, two, or three of R₁₈, R₁₉, R₂₀,R₂₁, R₂₂, and R₂₃ are N, none, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ is S(O)₂, and the others are C. Independently in someembodiments of Formula IX, and independently in combination with anyembodiments of any other relevant substituent classes, none, one, or twoof R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are N, none, one, or two of R₁₈,R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S(O)₂, and the others are C.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none or one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are N, none orone of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S(O)₂, and the others are C.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, andR₂₂ are N, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁,and R₂₂ is S(O)₂, and the others are C. Independently in someembodiments of Formula XIV, and independently in combination with anyembodiments of any other relevant substituent classes, none, one, two,three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are N, none, one, two,three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is S(O)₂, and the othersare C. Independently in some embodiments of Formula XIV, andindependently in combination with any embodiments of any other relevantsubstituent classes, none, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, andR₂₂ are N, none, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ areS(O)₂, and the others are C. Independently in some embodiments ofFormula XIV, and independently in combination with any embodiments ofany other relevant substituent classes, none, one or two of R₁₈, R₁₉,R₂₀, R₂₁, and R₂₂ are N, none, one or two of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂are S(O)₂, and the others are C. Independently in some embodiments ofFormula XIV, and independently in combination with any embodiments ofany other relevant substituent classes, none or one of R₁₈, R₁₉, R₂₀,R₂₁, and R₂₂ is N, none or one of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S(O)₂,and the others are C.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, andR₂₃ are N, one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S(O)₂, and theothers are C. Independently in some embodiments of Formula IX, andindependently in combination with any embodiments of any other relevantsubstituent classes, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are N, one or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ areS(O)₂, and the others are C. Independently in some embodiments ofFormula IX, and independently in combination with any embodiments of anyother relevant substituent classes, one, two, or three of R₁₈, R₁₉, R₂₀,R₂₁, R₂₂, and R₂₃ are N, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,and R₂₃ are S(O)₂, and the others are C. Independently in someembodiments of Formula IX, and independently in combination with anyembodiments of any other relevant substituent classes, one or two ofR₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are N, one, two, three, or four of R₁₈,R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S(O)₂, and the others are C.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is N, one, two, three,four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S(O)₂, and theothers are C.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are N,one of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is S(O)₂, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are N, one ortwo of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S(O)₂, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one or two of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are N, one, two, orthree of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S(O)₂, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is N, one, two, three, orfour of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S(O)₂, and the others are C.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, four, five, or six of R₁₈, R₁₉, R₂₀,R₂₁, R₂₂, and R₂₃ are O, none, one, two, three, four, five, or six ofR₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S, and the others are C.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are O, none, one, two, three, four, or five of R₁₈, R₁₉,R₂₀, R₂₁, R₂₂, and R₂₃ is S, and the others are C. Independently in someembodiments of Formula IX, and independently in combination with anyembodiments of any other relevant substituent classes, none, one, two,three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are O, none, one,two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S, and theothers are C. Independently in some embodiments of Formula IX, andindependently in combination with any embodiments of any other relevantsubstituent classes, none, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are O, none, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,and R₂₃ is S, and the others are C. Independently in some embodiments ofFormula IX, and independently in combination with any embodiments of anyother relevant substituent classes, none, one, or two of R₁₈, R₁₉, R₂₀,R₂₁, R₂₂, and R₂₃ are O, none, one, or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,and R₂₃ is S, and the others are C. Independently in some embodiments ofFormula IX, and independently in combination with any embodiments of anyother relevant substituent classes, none or one of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are O, none or one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ isS, and the others are C.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, andR₂₂ are O, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁,and R₂₂ is S, and the others are C. Independently in some embodiments ofFormula XIV, and independently in combination with any embodiments ofany other relevant substituent classes, none, one, two, three, or fourof R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are O, none, one, two, three, or four ofR₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is S, and the others are C. Independently insome embodiments of Formula XIV, and independently in combination withany embodiments of any other relevant substituent classes, none, one,two, or three of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are O, none, one, two, orthree of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, none, one or two of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are O, none,one or two of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, none or one of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is O, none or one ofR₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S, and the others are C.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, andR₂₃ are O, one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S, and the othersare C. Independently in some embodiments of Formula IX, andindependently in combination with any embodiments of any other relevantsubstituent classes, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are O, one or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ areS, and the others are C. Independently in some embodiments of FormulaIX, and independently in combination with any embodiments of any otherrelevant substituent classes, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are O, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, andR₂₃ are S, and the others are C. Independently in some embodiments ofFormula IX, and independently in combination with any embodiments of anyother relevant substituent classes, one or two of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are O, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,and R₂₃ are S, and the others are C. Independently in some embodimentsof Formula IX, and independently in combination with any embodiments ofany other relevant substituent classes, one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,and R₂₃ is N, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,and R₂₃ are S, and the others are C.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are O,one of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is S, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are O, one ortwo of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one or two of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are O, one, two, orthree of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is O, one, two, three, orfour of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S, and the others are C.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, four, five, or six of R₁₈, R₁₉, R₂₀,R₂₁, R₂₂, and R₂₃ are O, none, one, two, three, four, five, or six ofR₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S(O)₂, and the others are C.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are O, none, one, two, three, four, or five of R₁₈, R₁₉,R₂₀, R₂₁, R₂₂, and R₂₃ is S(O)₂, and the others are C. Independently insome embodiments of Formula IX, and independently in combination withany embodiments of any other relevant substituent classes, none, one,two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are O, none,one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S(O)₂,and the others are C. Independently in some embodiments of Formula IX,and independently in combination with any embodiments of any otherrelevant substituent classes, none, one, two, or three of R₁₈, R₁₉, R₂₀,R₂₁, R₂₂, and R₂₃ are O, none, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ is S(O)₂, and the others are C. Independently in someembodiments of Formula IX, and independently in combination with anyembodiments of any other relevant substituent classes, none, one, or twoof R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are O, none, one, or two of R₁₈,R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S(O)₂, and the others are C.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none or one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are O, none orone of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S(O)₂, and the others are C.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, andR₂₂ are O, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁,and R₂₂ is S(O)₂, and the others are C. Independently in someembodiments of Formula XIV, and independently in combination with anyembodiments of any other relevant substituent classes, none, one, two,three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are O, none, one, two,three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is S(O)₂, and the othersare C. Independently in some embodiments of Formula XIV, andindependently in combination with any embodiments of any other relevantsubstituent classes, none, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, andR₂₂ are O, none, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ areS(O)₂, and the others are C. Independently in some embodiments ofFormula XIV, and independently in combination with any embodiments ofany other relevant substituent classes, none, one or two of R₁₈, R₁₉,R₂₀, R₂₁, and R₂₂ are O, none, one or two of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂are S(O)₂, and the others are C. Independently in some embodiments ofFormula XIV, and independently in combination with any embodiments ofany other relevant substituent classes, none or one of R₁₈, R₁₉, R₂₀,R₂₁, and R₂₂ is O, none or one of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S(O)₂,and the others are C.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, andR₂₃ are O, one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S(O)₂, and theothers are C. Independently in some embodiments of Formula IX, andindependently in combination with any embodiments of any other relevantsubstituent classes, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are O, one or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ areS(O)₂, and the others are C. Independently in some embodiments ofFormula IX, and independently in combination with any embodiments of anyother relevant substituent classes, one, two, or three of R₁₈, R₁₉, R₂₀,R₂₁, R₂₂, and R₂₃ are O, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,and R₂₃ are S(O)₂, and the others are C. Independently in someembodiments of Formula IX, and independently in combination with anyembodiments of any other relevant substituent classes, one or two ofR₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are O, one, two, three, or four of R₁₈,R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S(O)₂, and the others are C.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is O, one, two, three,four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S(O)₂, and theothers are C.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are O,one of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is S(O)2, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are O, one ortwo of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S(O)₂, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one or two of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are O, one, two, orthree of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S(O)₂, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is O, one, two, three, orfour of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S(O)₂, and the others are C.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, four, five, or six of R₁₈, R₁₉, R₂₀,R₂₁, R₂₂, and R₂₃ are S, none, one, two, three, four, five, or six ofR₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S(O)₂, and the others are C.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are S, none, one, two, three, four, or five of R₁₈, R₁₉,R₂₀, R₂₁, R₂₂, and R₂₃ is S(O)₂, and the others are C. Independently insome embodiments of Formula IX, and independently in combination withany embodiments of any other relevant substituent classes, none, one,two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S, none,one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S(O)₂,and the others are C. Independently in some embodiments of Formula IX,and independently in combination with any embodiments of any otherrelevant substituent classes, none, one, two, or three of R₁₈, R₁₉, R₂₀,R₂₁, R₂₂, and R₂₃ are S, none, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ is S(O)₂, and the others are C. Independently in someembodiments of Formula IX, and independently in combination with anyembodiments of any other relevant substituent classes, none, one, or twoof R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S, none, one, or two of R₁₈,R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S(O)₂, and the others are C.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none or one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S, none orone of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S(O)₂, and the others are C.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, andR₂₂ are S, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁,and R₂₂ is S(O)₂, and the others are C. Independently in someembodiments of Formula XIV, and independently in combination with anyembodiments of any other relevant substituent classes, none, one, two,three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S, none, one, two,three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is S(O)₂, and the othersare C. Independently in some embodiments of Formula XIV, andindependently in combination with any embodiments of any other relevantsubstituent classes, none, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, andR₂₂ are S, none, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ areS(O)₂, and the others are C. Independently in some embodiments ofFormula XIV, and independently in combination with any embodiments ofany other relevant substituent classes, none, one or two of R₁₈, R₁₉,R₂₀, R₂₁, and R₂₂ are S, none, one or two of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂are S(O)₂, and the others are C. Independently in some embodiments ofFormula XIV, and independently in combination with any embodiments ofany other relevant substituent classes, none or one of R₁₈, R₁₉, R₂₀,R₂₁, and R₂₂ is S, none or one of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S(O)₂,and the others are C.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, andR₂₃ are S, one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S(O)₂, and theothers are C. Independently in some embodiments of Formula IX, andindependently in combination with any embodiments of any other relevantsubstituent classes, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are S, one or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ areS(O)₂, and the others are C. Independently in some embodiments ofFormula IX, and independently in combination with any embodiments of anyother relevant substituent classes, one, two, or three of R₁₈, R₁₉, R₂₀,R₂₁, R₂₂, and R₂₃ are S, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,and R₂₃ are S(O)₂, and the others are C. Independently in someembodiments of Formula IX, and independently in combination with anyembodiments of any other relevant substituent classes, one or two ofR₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S, one, two, three, or four of R₁₈,R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S(O)₂, and the others are C.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S, one, two, three,four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S(O)₂, and theothers are C.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S,one of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is S(O)₂, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S, one ortwo of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S(O)₂, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one or two of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S, one, two, orthree of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S(O)2, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, one of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is S, one, two, three, orfour of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are S(O)₂, and the others are C.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, four, five, or six of R₁₈, R₁₉, R₂₀,R₂₁, R₂₂, and R₂₃ are N, none, one, two, three, four, five, or six ofR₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S, none, one, two, three, four,five, or six of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is O, and the othersare C. Independently in some embodiments of Formula IX, andindependently in combination with any embodiments of any other relevantsubstituent classes, none, one, two, three, four, or five of R₁₈, R₁₉,R₂₀, R₂₁, R₂₂, and R₂₃ are N, none, one, two, three, four, or five ofR₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S, none, one, two, three, four, orfive of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is O, and the others are C.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, andR₂₃ are N, none, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,and R₂₃ are S, none, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ is O, and the others are C. Independently in someembodiments of Formula IX, and independently in combination with anyembodiments of any other relevant substituent classes, none, one, two,or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are N, none, one, two, orthree of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S, none, one, two, orthree of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is O, and the others are C.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are N,none, one, or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S, none, one,or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is O, and the others are C.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none or one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are N, none orone of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S, none or one of R₁₈, R₁₉,R₂₀, R₂₁, R₂₂, and R₂₃ is O, and the others are C.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, orR₂₂ are N, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁,or R₂₂ are S, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀,R₂₁, or R₂₂ is O, and the others are C. Independently in someembodiments of Formula XIV, and independently in combination with anyembodiments of any other relevant substituent classes, none, one, two,three, or four of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are N, none, one, two,three, or four of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are S, none, one, two,three, or four of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ is O, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are N,none, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are S, none, one,two, or three of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ is O, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, or two of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are N, none,one, or two of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are S, none, one, or two ofR₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ is O, and the others are C. Independently insome embodiments of Formula XIV, and independently in combination withany embodiments of any other relevant substituent classes, none or oneof R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are N, none or one of R₁₈, R₁₉, R₂₀, R₂₁,or R₂₂ are S, none or one of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ is O, and theothers are C.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, four, five, or six of R₁₈, R₁₉, R₂₀,R₂₁, R₂₂, and R₂₃ are N, none, one, two, three, four, five, or six ofR₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S(O)₂, none, one, two, three, four,five, or six of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is O, and the othersare C. Independently in some embodiments of Formula IX, andindependently in combination with any embodiments of any other relevantsubstituent classes, none, one, two, three, four, or five of R₁₈, R₁₉,R₂₀, R₂₁, R₂₂, and R₂₃ are N, none, one, two, three, four, or five ofR₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S(O)₂, none, one, two, three, four,or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is O, and the others are C.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, andR₂₃ are N, none, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,and R₂₃ are S(O)₂, none, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ is O, and the others are C. Independently in someembodiments of Formula IX, and independently in combination with anyembodiments of any other relevant substituent classes, none, one, two,or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are N, none, one, two, orthree of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S(O)₂, none, one, two, orthree of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is O, and the others are C.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are N,none, one, or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S(O)₂, none,one, or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is O, and the others areC. Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none or one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are N, none orone of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S(O)₂, none or one of R₁₈,R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is O, and the others are C.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, orR₂₂ are N, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁,or R₂₂ are S(O)₂, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀,R₂₁, or R₂₂ is O, and the others are C. Independently in someembodiments of Formula XIV, and independently in combination with anyembodiments of any other relevant substituent classes, none, one, two,three, or four of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are N, none, one, two,three, or four of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are S(O)₂, none, one, two,three, or four of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ is O, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are N,none, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are S(O)₂, none,one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ is O, and the othersare C. Independently in some embodiments of Formula XIV, andindependently in combination with any embodiments of any other relevantsubstituent classes, none, one, or two of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ areN, none, one, or two of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are S(O)₂, none, one,or two of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ is O, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, none or one of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are N, none or one ofR₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are S(O)₂, none or one of R₁₈, R₁₉, R₂₀, R₂₁,or R₂₂ is O, and the others are C.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, four, five, or six of R₁₈, R₁₉, R₂₀,R₂₁, R₂₂, and R₂₃ are N, none, one, two, three, four, five, or six ofR₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S, none, one, two, three, four,five, or six of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S(O)₂, and theothers are C.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are N, none, one, two, three, four, or five of R₁₈, R₁₉,R₂₀, R₂₁, R₂₂, and R₂₃ are S, none, one, two, three, four, or five ofR₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S(O)₂, and the others are C.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, andR₂₃ are N, none, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,and R₂₃ are S, none, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ is S(O)₂, and the others are C. Independently in someembodiments of Formula IX, and independently in combination with anyembodiments of any other relevant substituent classes, none, one, two,or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are N, none, one, two, orthree of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S, none, one, two, orthree of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S(O)₂, and the others areC. Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are N,none, one, or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S, none, one,or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is S(O)₂, and the others areC. Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none or one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are N, none orone of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S, none or one of R₁₈, R₁₉,R₂₀, R₂₁, R₂₂, and R₂₃ is S(O)₂, and the others are C.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, orR₂₂ are N, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁,or R₂₂ are S, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀,R₂₁, or R₂₂ is S(O)₂, and the others are C. Independently in someembodiments of Formula XIV, and independently in combination with anyembodiments of any other relevant substituent classes, none, one, two,three, or four of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are N, none, one, two,three, or four of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are S, none, one, two,three, or four of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ is S(O)₂, and the othersare C. Independently in some embodiments of Formula XIV, andindependently in combination with any embodiments of any other relevantsubstituent classes, none, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, orR₂₂ are N, none, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are S,none, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ is S(O)₂, and theothers are C. Independently in some embodiments of Formula XIV, andindependently in combination with any embodiments of any other relevantsubstituent classes, none, one, or two of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ areN, none, one, or two of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are S, none, one, ortwo of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ is S(O)₂, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, none or one of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are N, none or one ofR₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are S, none or one of R₁₈, R₁₉, R₂₀, R₂₁, orR₂₂ is S(O)₂, and the others are C.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, four, five, or six of R₁₈, R₁₉, R₂₀,R₂₁, R₂₂, and R₂₃ are S(O)₂, none, one, two, three, four, five, or sixof R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S, none, one, two, three, four,five, or six of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is O, and the othersare C. Independently in some embodiments of Formula IX, andindependently in combination with any embodiments of any other relevantsubstituent classes, none, one, two, three, four, or five of R₁₈, R₁₉,R₂₀, R₂₁, R₂₂, and R₂₃ are S(O)₂, none, one, two, three, four, or fiveof R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S, none, one, two, three, four,or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is O, and the others are C.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, andR₂₃ are S(O)₂, none, one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are S, none, one, two, three, or four of R₁₈, R₁₉, R₂₀,R₂₁, R₂₂, and R₂₃ is O, and the others are C. Independently in someembodiments of Formula IX, and independently in combination with anyembodiments of any other relevant substituent classes, none, one, two,or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S(O)₂, none, one, two,or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S, none, one, two, orthree of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is O, and the others are C.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ areS(O)₂, none, one, or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S,none, one, or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is O, and theothers are C. Independently in some embodiments of Formula IX, andindependently in combination with any embodiments of any other relevantsubstituent classes, none or one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ areS(O)₂, none or one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S, none orone of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is O, and the others are C.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, orR₂₂ are S(O)₂, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀,R₂₁, or R₂₂ are S, none, one, two, three, four, or five of R₁₈, R₁₉,R₂₀, R₂₁, or R₂₂ is O, and the others are C. Independently in someembodiments of Formula XIV, and independently in combination with anyembodiments of any other relevant substituent classes, none, one, two,three, or four of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are S(O)₂, none, one, two,three, or four of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are S, none, one, two,three, or four of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ is O, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ areS(O)₂, none, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are S,none, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ is O, and theothers are C. Independently in some embodiments of Formula XIV, andindependently in combination with any embodiments of any other relevantsubstituent classes, none, one, or two of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ areS(O)₂, none, one, or two of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are S, none, one,or two of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ is O, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, none or one of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are S(O)₂, none orone of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are S, none or one of R₁₈, R₁₉, R₂₀,R₂₁, or R₂₂ is O, and the others are C.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, four, five, or six of R₁₈, R₁₉, R₂₀,R₂₁, R₂₂, and R₂₃ are N, none, one, two, three, four, five, or six ofR₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S, none, one, two, three, four,five, or six of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S(O)₂, none, one,two, three, four, five, or six of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is O,and the others are C. Independently in some embodiments of Formula IX,and independently in combination with any embodiments of any otherrelevant substituent classes, none, one, two, three, four, or five ofR₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are N, none, one, two, three, four, orfive of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S, none, one, two, three,four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S(O)₂, none, one,two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is O, andthe others are C. Independently in some embodiments of Formula IX, andindependently in combination with any embodiments of any other relevantsubstituent classes, none, one, two, three, or four of R₁₈, R₁₉, R₂₀,R₂₁, R₂₂, and R₂₃ are N, none, one, two, three, or four of R₁₈, R₁₉,R₂₀, R₂₁, R₂₂, and R₂₃ are S, none, one, two, three, or four of R₁₈,R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S(O)₂, none, one, two, three, or four ofR₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is O, and the others are C.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃are N, none, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ areS, none, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ areS(O)₂, none, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ isO, and the others are C. Independently in some embodiments of FormulaIX, and independently in combination with any embodiments of any otherrelevant substituent classes, none, one, or two of R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are N, none, one, or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, andR₂₃ are S, none, one, or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ areS(O)₂, none, one, or two of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is O, andthe others are C. Independently in some embodiments of Formula IX, andindependently in combination with any embodiments of any other relevantsubstituent classes, none or one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ areN, none or one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S, none or one ofR₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are S(O)2, none or one of R₁₈, R₁₉,R₂₀, R₂₁, R₂₂, and R₂₃ is O, and the others are C.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁, orR₂₂ are N, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀, R₂₁,or R₂₂ are S, none, one, two, three, four, or five of R₁₈, R₁₉, R₂₀,R₂₁, or R₂₂ are S(O)₂, none, one, two, three, four, or five of R₁₈, R₁₉,R₂₀, R₂₁, or R₂₂ is O, and the others are C. Independently in someembodiments of Formula XIV, and independently in combination with anyembodiments of any other relevant substituent classes, none, one, two,three, or four of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are N, none, one, two,three, or four of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are S, none, one, two,three, or four of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are S(O)₂, none, one, two,three, or four of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ is O, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are N,none, one, two, or three of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are S, none, one,two, or three of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are S(O)₂, none, one, two,or three of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ is O, and the others are C.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, none, one, or two of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are N, none,one, or two of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are S, none, one, or two ofR₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are S(O)₂, none, one, or two of R₁₈, R₁₉,R₂₀, R₂₁, or R₂₂ is O, and the others are C. Independently in someembodiments of Formula XIV, and independently in combination with anyembodiments of any other relevant substituent classes, none or one ofR₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are N, none or one of R₁₈, R₁₉, R₂₀, R₂₁, orR₂₂ are S, none or one of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ are S(O)₂, none orone of R₁₈, R₁₉, R₂₀, R₂₁, or R₂₂ is O, and the others are C.

Independently in some embodiments of R₂₄, and independently incombination with any embodiments of any other relevant substituentclasses, R₂₄ can be

wherein k is an integer from 0 to 20;

wherein X_(d) are absent or O;

wherein R^(c) is R^(b), absent, hydrogen, U₃, U₃+Q₁; U₃+Q₂, U₃+Q₃,U₃+Q₄, U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄,U₃+Q₁+Q₂+Q₃, U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₄+Q₂+Q₃+Q₄,preferably U₃+Q₄+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independentlyR^(b), hydrogen, U₁, U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃,U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄,U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

Independently in some embodiments of R₂₄, and independently incombination with any embodiments of any other relevant substituentclasses, R₂₄ can be

wherein k is an integer from 1 to 20;

wherein X₄ are O;

wherein R^(c) is R^(b), absent, hydrogen, U₃, U₃+Q₁, U₃+Q₂, U₃+Q₃,U₃+Q₄, U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄,U₃+Q₁+Q₂+Q₃, U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄,preferably U₃+Q₁+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independentlyR^(b), hydrogen, U₁, U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃,U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₄+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄,U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

Independently in some embodiments of R₂₄, and independently incombination with any embodiments of any other relevant substituentclasses, R₂₄ can be

wherein k is an integer from 1 to 20;

wherein X_(d) are absent;

wherein R^(c) is R^(b), absent, hydrogen, U₃, U₃+Q₁, U₃+Q₂, U₃+Q₃,U₃+Q₄, U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄,U₃+Q₁+Q₂+Q₃, U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄,preferably U₃+Q₁+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independentlyR^(b), hydrogen U_(b) U₁+Q_(b) U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃,U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄,U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

Independently in some embodiments of R₂₄, and independently incombination with any embodiments of any other relevant substituentclasses, R₂₄ can be absent or —(CR₂₅R₂₅)_(p)—, wherein p is 1.

Independently in some embodiments of-A-B(—C)_(δ), —B(—C)_(δ), —B, C, R₆,R₈, R₉, R^(a), R^(b), R^(c), R^(d), and R^(e), and independently incombination with any embodiments of any other relevant substituentclasses, -A-B(—C)_(δ), —B(—C)_(δ), —B, C, R₆, R₈, R₉, R^(a), R^(b),R^(c), R^(d), and R^(e) can be, independently, an organic groupingcontaining any number of carbon atoms, 1-30 carbon atoms, 1-20 carbonatoms, or 1-14 carbon atoms, and optionally including one or moreheteroatoms such as oxygen, sulfur, or nitrogen grouping in linear,branched, or cyclic structural formats, representative R^(b) organicgroupings being those present in U₁; U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄,U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃,U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferablyU₁+Q₁+Q₃.

Independently in some embodiments of-A-B(—C)_(δ), —B(—C)_(δ), A, B, C,R₆, R₈, R₉, R^(a), R^(b), R^(c), R^(d), and R^(e), and independently incombination with any embodiments of any other relevant substituentclasses, -A-B(—C)_(δ), —B(—C)_(δ), A, B, C, R₆, R₈, R₉, R^(a), R^(b),R^(c), R^(d), and R^(e) can be, independently, U₁, U₁+Q₁, U₁+Q₂, U₁+Q₃,U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄,U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄,preferably U₁+Q₁+Q₃.

Independently in some embodiments of-A-B(—C)_(δ), —B(—C)_(δ), A, B, C,R₆, R₈, R₉, R^(a), R^(b), R^(c), R^(d), and R^(e), and independently incombination with any embodiments of any other relevant substituentclasses, -A-B(—C)_(δ), —B(—C)_(δ), A, B, C, R₆, R₈, R₉, R^(a), R^(b),R^(c), R^(d), and R^(e) can be, independently, amino, hydroxyl, thiol,oxo, phosphate, or J₁.

Independently in some embodiments of-A-B(—C)_(δ), —B(—C)_(δ), A, B, C,R₆, R₈, R₉, R^(a), R^(b), R^(c), R^(d), and R^(e), and independently incombination with any embodiments of any other relevant substituentclasses, -A-B(—C)_(δ), —B(—C)_(δ), A, B, C, R₆, R₈, R₉, R^(a), R^(b),R^(c), R^(d), and R^(e) can be, independently, amino, hydroxyl, thiol,oxo, phosphate, or J₂.

Independently in some embodiments of-A-B(—C)_(δ), —B(—C)_(δ), A, B, C,R₆, R₈, R₉, R^(a), R^(b), R^(c), R^(d), and R^(e), and independently incombination with any embodiments of any other relevant substituentclasses, -A-B(—C)_(δ), —B(—C)_(δ), A, B, C, R₆, R₈, R₉, R^(a), R^(b),R^(c), R^(d), and R^(e) can be, independently,

wherein y is an integer from 0-11; wherein w is an integer from 0-9;wherein k is an integer from 0 to 20;

wherein R^(d) are independently U₂, U₂+Q₁, U₂+Q₂, U₂+Q₃, U₂+Q₄,U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃, U₂+Q₂+Q₄, U₂+Q₃+Q₄, U₂+Q₁+Q₂+Q₃,U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄, and U₂+Q₁+Q₂+Q₃+Q₄, preferablyU₂+Q₁+Q₃; or together with the carbon atom to which they are attached,form a 3- to 8-membered unsubstituted or substituted carbocyclic orheterocyclic ring;

wherein X_(d) are independently absent, O, or S;

wherein R^(c) is absent, hydrogen, U₃, U₃+Q₁; U₃+Q₂, U₃+Q₃, U₃+Q₄,U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃,U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄, preferablyU₃+Q₁+Q₃;

wherein R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are independently C, O, N, S,S(O), or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₃ are doubleor single according to valency, and wherein R₁₈ to R₂₃ are bound tonone, one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)-, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyabsent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₄ is U₁, U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independentlyhydrogen, U₁, U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄,U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄,U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

Independently in some embodiments of-A-B(—C)_(δ), —B(—C)_(δ), A, B, C,R₆, R₈, R₉, R^(a), R^(b), R^(c), R^(d), and R^(e), and independently incombination with any embodiments of any other relevant substituentclasses, -A-B(—C)_(δ), —B(—C)_(δ), A, B, C, R₆, R₈, R₉, R^(a), R^(b),R^(c), R^(d), and R^(e) can be, independently,

wherein y is an integer from 0-11; wherein w is an integer from 0-9;

wherein R^(d) and R^(e) are independently U₂, U₂+Q₁, U₂+Q₂, U₂+Q₃,U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃, U₂+Q₂+Q₄, U₂+Q₃+Q₄,U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄, and U₂+Q₁+Q₂+Q₃+Q₄,preferably U₂+Q₁+Q₃; or together with the carbon atom to which they areattached, form a 3- to 8-membered unsubstituted or substitutedcarbocyclic or heterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are independently C, O, N, S,S(O), or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₃ are doubleor single according to valency, and wherein R₁₈ to R₂₃ are bound tonone, one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyabsent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₄ is U₁, U₁+Q₁;U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of-A-B(—C)_(δ), —B(—C)_(δ), A, B, C,R₆, R₈, R₉, R^(a), R^(b), R^(c), R^(d), and R^(e), and independently incombination with any embodiments of any other relevant substituentclasses, -A-B(—C)_(δ), —B(—C)_(δ), A, B, C, R₆, R₈, R₉, R^(a), R^(b),R^(c), R^(d), and R^(e) can be, independently,

wherein w is an integer from 0-9;

wherein R^(d) and R^(e) are independently U₂, U₂+Q₁, U₂+Q₂, U₂+Q₃,U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃, U₂+Q₂+Q₄, U₂+Q₃+Q₄,U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄, and U₂+Q₁+Q₂+Q₃+Q₄,preferably U₂+Q₁+Q₃; or together with the carbon atom to which they areattached, form a 3- to 8-membered unsubstituted or substitutedcarbocyclic or heterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are independently C, O, N, S, S(O),or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₂ are double orsingle according to valency, and wherein R₁₈ to R₂₂ are bound to none,one, or two hydrogens according to valency; and wherein R₂₄ areindependently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—,

wherein p and q are independently integers from 0 to 5, wherein X_(b) isabsent, —O—, —S—, —S(O)—, or —S(O)₂—, or NR₄, wherein each R₂₅ is, asvalency permits, independently absent, hydrogen, =O, ═S, —OH, —SH, or—NR₄, wherein R₄ is U₁; U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃,U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄,U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of-A-B(—C)_(δ), —B(—C)_(δ), A, B, C,R₆, R₈, R₉, R^(a), R^(b), R^(c), R^(d), and R^(e), and independently incombination with any embodiments of any other relevant substituentclasses, -A-B(—C)_(δ), —B(—C)_(δ), A, B, C, R₆, R₈, R₉, R^(a), R^(b),R^(c), R^(d), and R^(e) can be, independently,

wherein w is an integer from 0-9;

wherein R^(d) and R^(e) are independently U₂, U₂+Q₁, U₂+Q₂, U₂+Q₃,U₂+Q₄, U₂+Q₁+Q₂, U₂+Q₁+Q₃, U₂+Q₁+Q₄, U₂+Q₂+Q₃, U₂+Q₂+Q₄, U₂+Q₃+Q₄,U₂+Q₁+Q₂+Q₃, U₂+Q₁+Q₂+Q₄, U₂+Q₁+Q₃+Q₄, U₂+Q₂+Q₃+Q₄, and U₂+Q₁+Q₂+Q₃+Q₄,preferably U₂+Q₁+Q₃; or together with the carbon atom to which they areattached, form a 3- to 8-membered unsubstituted or substitutedcarbocyclic or heterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are independently C or N, whereinthe bonds between adjacent R₁₈ to R₂₂ are double or single according tovalency, wherein one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂are N and the others are C, and wherein R₁₈ to R₂₂ are bound to none,one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—, or—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyabsent, hydrogen, =O, ═S, —OH, —SH, or —NR₄, wherein R₄ is U₁; U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

Independently in some embodiments of-A-B(—C)_(δ), —B(—C)_(δ), A, B, C,R₆, R₈, R₉, R^(a), R^(b), R^(c), R^(d), and R^(e), and independently incombination with any embodiments of any other relevant substituentclasses, -A-B(—C)_(δ), —B(—C)_(δ), A, B, C, Rb, R₈, R₉, R^(a), R^(b),R^(c), R^(d), and R^(e) can be, independently,

wherein k is an integer from 0 to 20;

wherein X_(d) are independently absent, O, or S;

wherein R^(c) is absent, hydrogen, U₃, U₃+Q₁; U₃+Q₂, U₃+Q₃, U₃+Q₄,U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃,U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄, preferablyU₃+Q₁+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independentlyhydrogen, U₁, U₁+Q₁; U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄,U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄,U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

Independently in some embodiments of-A-B(—C)_(δ), —B(—C)_(δ), A, B, C,R₆, R₈, R₉, R^(a), R^(b), R^(c), R^(d), and R^(e), and independently incombination with any embodiments of any other relevant substituentclasses, -A-B(—C)_(δ), —B(—C)_(δ), A, B, C, R₆, R₈, R₉, R^(a), R^(b),R^(c), R^(d), and R^(e) can be, independently,

wherein k is an integer from 0 to 20;

wherein X₄ are independently O or S;

wherein R^(c) is absent, hydrogen, U₃, U₃+Q₁, U₃+Q₂, U₃+Q₃, U₃+Q₄,U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃,U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄, preferablyU₃+Q₁+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independentlyhydrogen, U₁, U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₄+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄,U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄,U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

Independently in some embodiments of-A-B(—C)_(δ), —B(—C)_(δ), A, B, C,R₆, R₈, R₉, R^(a), R^(b), R^(c), R^(d), and R^(e), and independently incombination with any embodiments of any other relevant substituentclasses, -A-B(—C)_(δ), —B(—C)_(δ), A, B, C, R₆, R₈, R₉, R^(a), R^(b),R^(c), R^(d), and R^(e) can be, independently,

wherein k is an integer from 1 to 20;

wherein X_(d) are O;

wherein R^(c) is absent, hydrogen, U₃, U₃+Q₁, U₃+Q₂, U₃+Q₃, U₃+Q₄,U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃,U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄, preferablyU₃+Q₁+Q₃; and

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independentlyhydrogen, U₁, U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄,U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄,U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

In some embodiments, y in Formula IX is an integer from 0-3; R^(e) isindependently amino, hydroxyl, thiol, oxo, phosphate, or substituted orunsubstituted Cr C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylamino, or C₁-C₆alkylthio;

where R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are independently C, O, N, or S,where the bonds between adjacent R₁₈ to R₂₃ are double or singleaccording to valency, and where R₁₈ to R₂₃ are bound to none, one, ortwo hydrogens according to valency; and

where R₂₄ is independently —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, where p and q are independentlyintegers from 0 to 3, where X_(b) is absent, —O—, —S—, —SO₂—, or NR₄,where each R₂₅ is, as valency permits, independently absent, hydrogen,=O, ═S, —OH, —SH, —NR₄, where R₄ is substituted or unsubstituted C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylamino, or C₁-C₆ alkylthio.

In some embodiments, y in Formula IX is 2, R₁₈ is N, R₁₉, R₂₀, R₂₁, R₂₂,or R₂₃ is S, both R^(e) are oxo and are bonded to the S, and all of thebonds between adjacent R₁₈ to R₂₃ are single.

In some embodiments, y in Formula IX is 2, both R^(e) are oxo and arebonded to R₂₁, R₁₈ is N, R₂₁ is S, and all of the bonds between adjacentR₁₈ to R₂₃ are single.

In some embodiments, y in Formula IX is 2, both R^(e) are oxo and arebonded to R₂₁, R₁₈ is N, R₂₁ is S, and all of the bonds between adjacentR₁₈ to R₂₃ are single, X_(b) is absent, q is 0, p is 1, and each R₂₅ ishydrogen.

In some embodiments, y in Formula IX is 1, R^(e) is amino, and three ofthe bonds between adjacent R₁₈ to R₂₃ are double and three of the bondsbetween adjacent R₁₈ to R₂₃ are single.

In some embodiments, y in Formula IX is 1, R^(e) is amino and is bondedto R₂₁, and three of the bonds between adjacent R₁₈ to R₂₃ are doubleand three of the bonds between adjacent R₁₈ to R₂₃ are single.

In some embodiments, y in Formula IX is 1, R^(e) is amino and is bondedto R₂₁, and three of the bonds between adjacent R₁₈ to R₂₃ are doubleand three of the bonds between adjacent R₁₈ to R₂₃ are single, X_(b) isabsent, p is 0 and q is 0.

In some embodiments, y in Formula IX is 0, R₁₉, R₂₀, R₂₁, R₂₂, or R₂₃ isO, and all of the bonds between adjacent R₁₈ to R₂₃ are single.

In some embodiments, y in Formula IX is 0, R₁₉ is O, and all of thebonds between adjacent R₁₈ to R₂₃ are single.

In some embodiments, y in Formula IX is 0, R₁₉ is O, all of the bondsbetween adjacent R₁₈ to R₂₃ are single, X_(b) is oxygen, p is 1, q is 0and each R₂₅ is hydrogen.

In some embodiments, R₁₉ and R₂₃ of Formula IX are O and all of thebonds between adjacent R₁₈ to R₂₃ are single.

In some embodiments, R₁₉ and R₂₃ of Formula IX are O, the bonds betweenR₁₈ and R₁₉, and between R₂₁ and R₂₂ are double bonds, and the rest ofthe bonds in the ring are single bonds.

In some embodiments, y in Formula IX is 1, R^(e) is alkoxy and is bondedto R₁₉, R₂₀, R₂₁, R₂₁, R₂₂, or R₂₃, three of the bonds between adjacentR₁₈ to R₂₃ are double and three of the bonds between adjacent R₁₈ to R₂₃are single.

In some embodiments, y in Formula IX is 1, R^(e) is alkoxy and is bondedto R₁₉, three of the bonds between adjacent R₁₈ to R₂₃ are double andthree of the bonds between adjacent R₁₈ to R₂₃ are single.

In some embodiments, y in Formula IX is 1, R^(e) is methoxy, and isbonded to R₁₉, R₁₈ to R₂₃ are carbon atoms, three of the bonds betweenadjacent R₁₈ to R₂₃ are double and three of the bonds between adjacentR₁₈ to R₂₃ are single, X_(b) is absent, p is 0 and q is 0.

In some embodiments, y in Formula IX is 1, R^(e) is hydroxyl.

In some embodiments, y in Formula IX is 1 and R^(e) is hydroxyl bondedat the position para- to the methylene group.

In some embodiments, y in Formula IX is 1, R^(e) is Formula XIII shownbelow:

wherein R₈ is a substituted alkyl and R₉ is a dialkylamino, or R₈ is adialkylamino and R₉ is a substituted alkyl, wherein the substitutedalkyl is hydroxymethyl and the dialkylamino is XX-diethylamino.

In some embodiments, y in Formula IX is 1, R^(e) is Formula XIII,wherein R₈ is hydrogen and R₉ is Formula IX shown below:

or R₈ is Formula IX and R₉ is hydrogen. In some embodiments, y inFormula IX is 0, R₁₉, R₂₀, R₂₁, R₂₂, or R₂₃ is O, and all of the bondsbetween adjacent R₁₈ to R₂₃ are single. In some embodiments, y inFormula IX is 0, R₁₉ is O, and all of the bonds between adjacent R₁₈ toR₂₃ are single. In some embodiments, y in Formula IX is 0, R₁₉ is O, allof the bonds between adjacent R₁₈ to R₂₃ are single, X_(b) is oxygen, pis 1, q is 0 and each R₂₅ is hydrogen.

In some embodiments, y in Formula IX is 1, R^(e) is Formula XIII,wherein R₈ is hydrogen and R₉ is Formula VII or Formula VIII shownbelow:

wherein R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are, independently, hydrogen,U. U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃;

wherein R₃₁, R₃₄, R₃₅, and R₃₆ are independently present or absentaccording to valency, and wherein the ring bonds are double or singleaccording to valency.

In some embodiments R₃₁ of Formula VII is alkyl. In some embodiments,R₃₁ is methyl.

In some embodiments R₃₁ of Formula VII is methyl, R₃₂ and R₃₃ arehydrogen.

In some embodiments, y in Formula IX is 1 and R^(e) is hydroxyl bondedat the position para- to the methylene group.

In some embodiments of Formula XII, k is 1 and R^(c) is hydroxyl.

In some embodiments of Formula XII, k is 1, R^(c) is hydroxyl, and X_(d)is absent.

In some embodiments of Formula XII, k is 1, R^(c) is hydroxyl, X_(d) isabsent, and R₁₀-R₁₇ are hydrogen.

In some embodiments of Formula XII, R^(c) is alkoxy.

In some embodiments of Formula XII, R^(c) is methoxy and X_(d) is O.

In some embodiments of Formula XII, R^(c) is methoxy, X_(d) is O, andR₁₀-R₁₇ are hydrogen.

In some embodiments of Formula XII, k is 2 and R^(c) is alkylamino.

In some embodiments of Formula XII, k is 2, R^(c) is methylamino, andX_(d) is absent.

In some embodiments of Formula XII, k is 2, R^(c) is methylamino, X_(d)is absent, and R₁₀-R₁₇ are hydrogen.

In some embodiments of Formula XII, k is 3, X_(d) is O and R^(c) isFormula XIII shown below:

wherein R₈ and R₉ are alkyl.

In some embodiments of Formula XII, k is 3, X₄ is O, and R^(c) isFormula XIII, wherein R₈ and R₉ are methyl.

In some embodiments of Formula XII, k is 3, X₄ is O and R_(c) is FormulaXIII, wherein R₈ is hydrogen, and R₉ is carbonyl, or R₈ is carbonyl, andR₉ is hydrogen.

In some embodiments of Formula XII, k is 3, X₄ is O and R_(c) is FormulaXIII, wherein R₈ is hydrogen, and R₉ is acetyl, or R₈ is acetyl, and R₉is hydrogen.

In some embodiments of Formula XII, k is 3 and R_(c) is Formula XIII, R₈is hydrogen, and R₉ is Formula IX shown below:

or R₈ is hydrogen and R₉ is Formula IX.

In some embodiments of Formula XII, k is 3 and R_(c) is Formula XIII,wherein R₈ is hydrogen, and R₉ is Formula IX, or R₈ is hydrogen and R₉is Formula IX, wherein y in Formula IX is 2, R₁₈ is N, R₁₉, R₂₀, R₂₁,R₂₂, or R₂₃ is S, both R_(e) are oxo and are bonded to the S, and all ofthe bonds between adjacent R₁₈ to R₂₃ are single.

In some embodiments of Formula XII, k is 3 and R_(c) is Formula XIII,wherein R₈ is hydrogen, and R₉ is Formula IX, or R₈ is hydrogen and R₉is Formula IX, wherein y in Formula IX is 2, both R_(e) are oxo and arebonded to R₂₁, R₁₈ is N, R₂₁ is S, and all of the bonds between adjacentR₁₈ to R₂₃ are single.

In some embodiments of Formula XII, k is 3 and R_(c) is Formula XIII,wherein R₈ is hydrogen, and R₉ is Formula IX, or R₈ is hydrogen and R₉is Formula IX, wherein y in Formula IX is 2, both R_(e) are oxo and arebonded to R₂₁, R₁₈ is N, R₂₁ is S, and all of the bonds between adjacentR₁₈ to R₂₃ are single, X_(b) is absent, q is 0, p is 1, and each R₂₅ ishydrogen.

In some embodiments of Formula XII, k is 3 and R^(c) is Formula XIII,wherein R₈ is hydrogen, and R₉ is Formula IX, or R₈ is hydrogen and R₉is Formula IX, wherein y in Formula IX is 1, R^(e) is amino, and threeof the bonds between adjacent R₁₈ to R₂₃ are double and three of thebonds between adjacent R₁₈ to R₂₃ are single.

In some embodiments of Formula XII, k is 3 and R^(c) is Formula XIII,wherein R₈ is hydrogen, and R₉ is Formula IX, or R₈ is hydrogen and R₉is Formula IX, wherein y in Formula IX is 1, R^(e) is amino and isbonded to R₂₁, and three of the bonds between adjacent R₁₈ to R₂₃ aredouble and three of the bonds between adjacent R₁₈ to R₂₃ are single.

In some embodiments of Formula XII, k is 3 and R^(c) is Formula XIII,wherein R₈ is hydrogen, and R₉ is Formula IX, or R₈ is hydrogen and R₉is Formula IX, wherein y in Formula IX is 1, R^(e) is amino and isbonded to R₂₁, and three of the bonds between adjacent R₁₈ to R₂₃ aredouble and three of the bonds between adjacent R₁₈ to R₂₃ are single,X_(b) is absent, p is 0 and q is 0.

In some embodiments of Formula XII, k is 3 and R^(c) is Formula XIII,wherein R₈ is hydrogen, and R₉ is Formula IX, or R₈ is hydrogen and R₉is Formula IX, wherein y in Formula IX is 0, R₁₉, R₂₀, R₂₁, R₂₂, or R₂₃is O, and all of the bonds between adjacent R₁₈ to R₂₃ are single.

In some embodiments of Formula XII, k is 3 and R^(c) is Formula XIII,wherein R₈ is hydrogen, and R₉ is Formula IX, or R₈ is hydrogen and R₉is Formula IX, wherein y in Formula IX is 0, R₁₉ is O, and all of thebonds between adjacent R₁₈ to R₂₃ are single.

In some embodiments of Formula XII, k is 3 and R^(c) is Formula XIII,wherein R₈ is hydrogen, and R₉ is Formula IX, or R₈ is hydrogen and R₉is Formula IX, wherein y in Formula IX is 0, R₁₉ is O, all of the bondsbetween adjacent R₁₈ to R₂₃ are single, X_(b) is oxygen, p is 1, q is 0and each R₂₅ is hydrogen.

In some embodiments of Formula XII, k is 3 and R^(c) is Formula XIII,wherein R₈ is hydrogen, and R₉ is Formula IX, or R₈ is hydrogen and R₉is Formula IX, wherein y in Formula IX is 1, R^(e) is alkoxy and isbonded to R₁₉, R₂₀, R₂₁, R₂₁, R₂₂, or R₂₃, three of the bonds betweenadjacent R₁₈ to R₂₃ are double and three of the bonds between adjacentR₁₈ to R₂₃ are single.

In some embodiments of Formula XII, k is 3 and R^(c) is Formula XIII,wherein R₈ is hydrogen, and R₉ is Formula IX, or R₈ is hydrogen and R₉is Formula IX, wherein y in Formula IX is 1, R^(e) is alkoxy and isbonded to R₁₉, three of the bonds between adjacent R₁₈ to R₂₃ are doubleand three of the bonds between adjacent R₁₈ to R₂₃ are single.

In some embodiments of Formula XII, k is 3 and R^(c) is Formula XIII,wherein R₈ is hydrogen, and R₉ is Formula IX, or R₈ is hydrogen and R₉is Formula IX, wherein y in Formula IX is 1, R^(e) is alkoxy such asmethoxy, and is bonded to R₁₉, R₁₈ to R₂₃ are carbon atoms, three of thebonds between adjacent R₁₈ to R₂₃ are double and three of the bondsbetween adjacent R₁₈ to R₂₃ are single, X_(b) is absent, p is 0 and q is0.

In some embodiments, y in Formula XIV is 0, R₁₉, R₂₀, R₂₁, R₂₁, or R₂₂is O, and, as valency permits, two of the bonds between adjacent R₁₈ toR₂₂ are double bonds, and three of the bonds between adjacent R₁₈ to R₂₂are single bonds.

In some embodiments, y in Formula XIV is 0, R₁₉ is O, R₁₈, R₂₀, R₂₁ andR₂₂ are C, the bonds between R₁₈ and R₂₂, and between R₂₀ and R₂₁, aredouble bonds, and the rest of the bonds in the ring are single bonds.

In some embodiments, y in Formula XIV is 0, R₁₉ is O, R₁₈, R₂₀, R₂₁ andR₂₂ are C, the bonds between R₁₈ and R₂₂, and between R₂₀ and R₂₁, aredouble bonds, the rest of the bonds in the ring are single bonds, X_(b)is absent, p is 1, q is 0, and each R₂₅ is hydrogen.

In some embodiments, y in Formula XIV is 0, R₁₉, R₂₀, R₂₁, or R₂₂ is O,and, the bonds between adjacent R₁₈ to R₂₂ are single bonds.

In some embodiments, y in Formula XIV is 0, R₁₉ is O, R₁₈, R₂₀, R₂₁ andR₂₂ are C, and the bonds between adjacent R₁₈ to R₂₂ are single bonds.

In some embodiments, y in Formula XIV is 0, R₁₉ is O, R₁₈, R₂₀, R₂₁ andR₂₂ are C, the bonds between adjacent R₁₈ to R₂₂ are single bonds, X_(b)is absent, p is 1, q is 0, and each R₂₅ is hydrogen.

In some embodiments, y in Formula XIV is 0, R₁₉ and R₂₂ are O, and thebonds between adjacent R₁₈ to R₂₂ are single bonds.

In some embodiments, y in Formula XIV is 0, R₁₉ and R₂₂ are O, R₁₈, R₂₀and R₂₁ are C, the bonds between adjacent R₁₈ to R₂₂ are single bonds.

In some embodiments, y in Formula XIV is 0, R₁₉ and R₂₂ are O, R₁₈, R₂₀and R₂₁ are C, the bonds between adjacent R₁₈ to R₂₂ are single bonds,X_(b) is absent, p is 1, q is 0, and each R₂₅ is hydrogen.

In some embodiments, y in Formula XIV is 0, R₁₉, R₂₀, R₂₁, R₂₁, or R₂₂is N, and, as valency permits, two of the bonds between adjacent R₁₈ toR₂₂ are double bonds, and three of the bonds between adjacent R₁₈ to R₂₂are single bonds.

In some embodiments, y in Formula XIV is 0, R₁₉ is N, R₁₈, R₂₀, R₂₁ andR₂₂ are C, the bonds between R₁₈ and R₂₂, and between R₂₀ and R₂₁, aredouble bonds, and the rest of the bonds in the ring are single bonds.

In some embodiments, y in Formula XIV is 0, R₁₉ is N, R₁₈, R₂₀, R₂₁ andR₂₂ are C, the bonds between R₁₈ and R₂₂, and between R₂₀ and R₂₁, aredouble bonds, the rest of the bonds in the ring are single bonds, X_(b)is absent, p is 1, q is 0, and each R₂₅ is hydrogen.

In some embodiments, y in Formula XIV is 0, R₁₉, R₂₀, R₂₁, or R₂₂ is N,and, the bonds between adjacent R₁₈ to R₂₂ are single bonds.

In some embodiments, y in Formula XIV is 0, R₁₉ is N, R₁₈, R₂₀, R₂₁ andR₂₂ are C, and the bonds between adjacent R₁₈ to R₂₂ are single bonds.

In some embodiments, y in Formula XIV is 0, R₁₉ is N, R₁₈, R₂₀, R₂₁ andR₂₂ are C, the bonds between adjacent R₁₈ to R₂₂ are single bonds, X_(b)is absent, p is 1, q is 0, and each R₂₅ is hydrogen.

In some embodiments, y in Formula XIV is 0, R₁₉ and R₂₂ are N, and thebonds between adjacent R₁₈ to R₂₂ are single bonds.

In some embodiments, y in Formula XIV is 0, R₁₉ and R₂₂ are N, R₁₈, R₂₀and R₂₁ are C, the bonds between adjacent R₁₈ to R₂₂ are single bonds.

In some embodiments, y in Formula XIV is 0, R₁₉ and R₂₂ are N, R₁₈, R₂₀and R₂₁ are C, the bonds between adjacent R₁₈ to R₂₂ are single bonds,X_(b) is absent, p is 1, q is 0, and each R₂₅ is hydrogen.

In some embodiments, y in Formula XIV is 0, R₁₉, R₂₀, R₂₁, R₂₁, or R₂₂is S, and, as valency permits, two of the bonds between adjacent R₁₈ toR₂₂ are double bonds, and three of the bonds between adjacent R₁₈ to R₂₂are single bonds.

In some embodiments, y in Formula XIV is 0, R₁₉ is S, R₁₈, R₂₀, R₂₁ andR₂₂ are C, the bonds between R₁₈ and R₂₂, and between R₂₀ and R₂₁, aredouble bonds, and the rest of the bonds in the ring are single bonds.

In some embodiments, y in Formula XIV is 0, R₁₉ is S, R₁₈, R₂₀, R₂₁ andR₂₂ are C, the bonds between R₁₈ and R₂₂, and between R₂₀ and R₂₁, aredouble bonds, the rest of the bonds in the ring are single bonds, X_(b)is absent, p is 1, q is 0, and each R₂₅ is hydrogen.

In some embodiments, y in Formula XIV is 0, R₁₉, R₂₀, R₂₁, or R₂₂ is S,and, the bonds between adjacent R₁₈ to R₂₂ are single bonds.

In some embodiments, y in Formula XIV is 0, R₁₉ is S, R₁₈, R₂₀, R₂₁ andR₂₂ are C, and the bonds between adjacent R₁₈ to R₂₂ are single bonds.

In some embodiments, y in Formula XIV is 0, R₁₉ is S, R₁₈, R₂₀, R₂₁ andR₂₂ are C, the bonds between adjacent R₁₈ to R₂₂ are single bonds, X_(b)is absent, p is 1, q is 0, and each R₂₅ is hydrogen.

In some embodiments, y in Formula XIV is 0, R₁₉ and R₂₂ are S, and thebonds between adjacent R₁₈ to R₂₂ are single bonds.

In some embodiments, y in Formula XIV is 0, R₁₉ and R₂₂ are S, R₁₈, R₂₀and R₂₁ are C, the bonds between adjacent R₁₈ to R₂₂ are single bonds.

In some embodiments, y in Formula XIV is 0, R₁₉ and R₂₂ are S, R₁₈, R₂₀and R₂₁ are C, the bonds between adjacent R₁₈ to R₂₂ are single bonds,X_(b) is absent, p is 1, q is 0, and each R₂₅ is hydrogen.

In some embodiments R₃₇ of Formula XV is Si, and X_(g) is alkynyl.

In some embodiments R₃₇ of Formula XV is Si, X_(g) is ethynyl, and R₃₈is alkylene.

In some embodiments R₃₇ of Formula XV is Si, X_(g) is ethynyl, R₃₈ ismethylene, and R₃₉, R₄₀, and R₄₁ are alkyl.

In some embodiments R₃₇ of Formula XV is Si, X_(g) is ethynyl, R₃₈ ismethylene, and R₃₉, R₄₀, and R₄₁ are methyl.

Modified alginates can be either singularly modified alginate polymersor multiply modified alginate polymers. Singularly modified alginatepolymers are alginate polymers that contain one or more covalentlymodified monomers, wherein substantially all of the covalently modifiedmonomers possess the same covalent modification (i.e. the polymercontains one ‘type’ or species of covalently modified monomer). Multiplymodified alginate polymers are alginate polymers that contain covalentlymodified monomers, wherein substantially all of the covalently modifiedmonomers do not possess the same covalent modification (i.e. the polymercontains two or more ‘types’ or species of covalently modifiedmonomers).

In some embodiments, the modified alginate polymer is a singularlymodified alginate polymer. In some embodiments, the modified alginatepolymer is one of the singularly modified alginate polymers shown below:

In preferred embodiments, the modified alginate polymer is a multiplymodified alginate polymer possessing a polysaccharide backbonecontaining mannuronate monomers, guluronate monomers, a first species ortype of covalently modified monomer defined by Formula I, and a secondspecies or type of covalently modified monomer defined by Formula I. Insome embodiments, the modified alginate polymer is one of the multiplymodified alginate polymers shown below.

In some embodiments, multiply modified alginates are alginate polymersthat contain one or more covalently modified monomers having a structureaccording to Formula III, Formula IIIa, Formula IIIb, or a combinationof Formula IIIa and Formula IIIb

wherein, for Formula III, Formula IIIa or Formula IIIb,

X is oxygen, sulfur, or NR₄;

R₁; R₆, R₇, R₈, and R₉ are, independently, hydrogen or an organicgrouping containing any number of carbon atoms, 1-30 carbon atoms, 1-20carbon atoms, or 1-14 carbon atoms, and optionally including one or moreheteroatoms such as oxygen, sulfur, or nitrogen grouping in linear,branched, or cyclic structural formats, representative organic groupingsbeing those present in U₁, U₁+Q₁; U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂,U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃,U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferablyU₁+Q₁+Q₂+Q₃;

wherein

Y₁ and Y₂ independently are hydrogen or —PO(OR₅)₂; or

Y₂ is absent, and Y₁, together with the two oxygen atoms to which Y₁ andY₂ are attached form a cyclic structure as shown in Formula IV, FormulaIVa, Formula IVb, or a combination of Formula IVa and Formula IVb

wherein, for Formula IV, Formula IVa and Formula IVb

R₂ and R₃ are, independently, hydrogen or an organic grouping containingany number of carbon atoms, 1-30 carbon atoms, 1-20 carbon atoms, or1-14 carbon atoms, and optionally including one or more heteroatoms suchas oxygen, sulfur, or nitrogen grouping in linear, branched, or cyclicstructural formats, representative R₂ and R₃ groupings being thosepresent in U₁; U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄,U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄,U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃: or

R₂ and R₃, together with the carbon atom to which they are attached,form a 3- to 8-membered unsubstituted or substituted carbocyclic orheterocyclic ring; and

R₄ and R₅ are, independently, hydrogen or an organic grouping containingany number of carbon atoms, 1-30 carbon atoms, 1-20 carbon atoms, or1-14 carbon atoms, and optionally including one or more heteroatoms suchas oxygen, sulfur, or nitrogen grouping in linear, branched, or cyclicstructural formats, representative R₄ and R₅ groupings being thosepresent in U₁; U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄,U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄,U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

In some embodiments, R₈, R₉, or both are, independently, hydrogen,

wherein R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are, independently, hydrogen,U. U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃;

wherein R₃₁, R₃₄, R₃₅, and R₃₆ are independently present or absentaccording to valency, and wherein the ring bonds are double or singleaccording to valency.

In some embodiments, R is

(A)

wherein k is independently an integer from 1 to 30; wherein z is aninteger from 0 to 4; wherein X₄ is O or S; wherein R₁₀, R₁₁, R₁₂, R₁₃,R₁₄, R₁₅, R₁₆, and R₁₇ are independently hydrogen, U₁; U₁+Q₁, U₁+Q₂,U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃; and wherein R^(a) and R^(c) areindependently U₃, U₃+Q₁; U₃+Q₂, U₃+Q₃, U₃+Q₄, U₃+Q₂+Q₂, U₃+Q₂+Q₃,U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃, U₃+Q₁+Q₂+Q₄,U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄, preferably U₃+Q₁+Q₃; ortogether with the carbon atom to which they are attached, form a 3- to8-membered unsubstituted or substituted carbocyclic, heterocyclic ringor

wherein R₈, R₉, or both are, independently, hydrogen,

wherein R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are, independently, hydrogen,U. U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃;

wherein R₃₁, R₃₄, R₃₅, and R₃₆ are independently present or absentaccording to valency, and wherein the ring bonds are double or singleaccording to valency.

It should be understood that Formula III, Formula IIIa, and Formula IIIbalso represent a singly modified alginate, such as when X is —NR₇ and R₁is

In some embodiments, the modified alginates are alginate polymers thatcontain one or more covalently modified alginates units described byFormula I, Formula Ia, Formula Ib, combinations of Formula Ia andFormula Ib, Formula II, Formula IIa, Formula IIb, combinations ofFormula IIa and Formula IIb, Formula III, Formula IIIa, Formula IIIb,combinations of Formula IIIa and Formula IIIb, Formula IV, Formula IVa,Formula IVb or combinations of Formula IVa and Formula IVb, wherein foreach formula R₂, R₃, R₄, R₅, R₆, R₇, R₈, and R₉ are independentlyhydrogen or an organic grouping containing any number of carbon atoms,1-30 carbon atoms, 1-20 carbon atoms, or 1-14 carbon atoms, andoptionally including one or more heteroatoms such as oxygen, sulfur, ornitrogen grouping in linear, branched, or cyclic structural formats,representative organic groupings being those present in U₁, U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₄+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,Q₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃; or R₂ and R₃, together with thecarbon atom to which they are attached, form a 3- to 8-memberedunsubstituted or substituted carbocyclic or heterocyclic ring; andwherein R₁ is not hydrogen or an organic grouping containing any numberof carbon atoms, 1-30 carbon atoms, 1-20 carbon atoms, or 1-14 carbonatoms, and optionally including one or more heteroatoms such as oxygen,sulfur, or nitrogen grouping in linear, branched, or cyclic structuralformats, representative organic groupings being those present in U₁;U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

In some embodiments, the modified alginates are alginate polymers thatcontain one or more covalently modified alginates units described byFormula I, Formula Ia, Formula Ib, combinations of Formula Ia andFormula Ib, Formula II, Formula IIa, Formula IIb, combinations ofFormula IIa and Formula IIb, Formula III, Formula IIIa, Formula IIIb,combinations of Formula IIIa and Formula IIIb, Formula IV, Formula IVa,Formula IVb or combinations of Formula IVa and Formula IVb, wherein foreach formula R₁; R₃, R₄, R₅, R₆, R₇, R₈, and R₉ are independentlyhydrogen or an organic grouping containing any number of carbon atoms,1-30 carbon atoms, 1-20 carbon atoms, or 1-14 carbon atoms, andoptionally including one or more heteroatoms such as oxygen, sulfur, ornitrogen grouping in linear, branched, or cyclic structural formats,representative organic groupings being those present in U₁, U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₄+Q₂+Q₃, U₄+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃; or R₂ and R₃, together with thecarbon atom to which they are attached, form a 3- to 8-memberedunsubstituted or substituted carbocyclic or heterocyclic ring; andwherein R₂ is not hydrogen or an organic grouping containing any numberof carbon atoms, 1-30 carbon atoms, 1-20 carbon atoms, or 1-14 carbonatoms, and optionally including one or more heteroatoms such as oxygen,sulfur, or nitrogen grouping in linear, branched, or cyclic structuralformats, representative organic groupings being those present in U₁;U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

In some embodiments, the modified alginates are alginate polymers thatcontain one or more covalently modified alginates units described byFormula I, Formula Ia, Formula Ib, combinations of Formula Ia andFormula Ib, Formula II, Formula IIa, Formula IIb, combinations ofFormula IIa and Formula IIb, Formula III, Formula IIIa, Formula IIIb,combinations of Formula IIIa and Formula IIIb, Formula IV, Formula IVa,Formula IVb or combinations of Formula IVa and Formula IVb, wherein foreach formula R₁; R₂, R₄, R₅, R₆, R₇, R₈, and R₉ are independentlyhydrogen or an organic grouping containing any number of carbon atoms,1-30 carbon atoms, 1-20 carbon atoms, or 1-14 carbon atoms, andoptionally including one or more heteroatoms such as oxygen, sulfur, ornitrogen grouping in linear, branched, or cyclic structural formats,representative organic groupings being those present in U₁; U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃; or R₂ and R₃, together with thecarbon atom to which they are attached, form a 3- to 8-memberedunsubstituted or substituted carbocyclic or heterocyclic ring; andwherein R₃ is not hydrogen or an organic grouping containing any numberof carbon atoms, 1-30 carbon atoms, 1-20 carbon atoms, or 1-14 carbonatoms, and optionally including one or more heteroatoms such as oxygen,sulfur, or nitrogen grouping in linear, branched, or cyclic structuralformats, representative organic groupings being those present in U₁,U₁+Q₁; U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

In some embodiments, the modified alginates are alginate polymers thatcontain one or more covalently modified alginates units described byFormula I, Formula Ia, Formula Ib, combinations of Formula Ia andFormula Ib, Formula II, Formula IIa, Formula IIb, combinations ofFormula IIa and Formula IIb, Formula III, Formula IIIa, Formula IIIb,combinations of Formula IIIa and Formula IIIb, Formula IV, Formula IVa,Formula IVb or combinations of Formula IVa and Formula IVb, wherein foreach formula R₁; R₂, R₃, R₅, R₆, R₇, R₈, and R₉ are independentlyhydrogen or an organic grouping containing any number of carbon atoms,1-30 carbon atoms, 1-20 carbon atoms, or 1-14 carbon atoms, andoptionally including one or more heteroatoms such as oxygen, sulfur, ornitrogen grouping in linear, branched, or cyclic structural formats,representative organic groupings being those present in U₁; U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃; or R₂ and R₃, together with thecarbon atom to which they are attached, form a 3- to 8-memberedunsubstituted or substituted carbocyclic or heterocyclic ring; andwherein R₄ is not hydrogen or an organic grouping containing any numberof carbon atoms, 1-30 carbon atoms, 1-20 carbon atoms, or 1-14 carbonatoms, and optionally including one or more heteroatoms such as oxygen,sulfur, or nitrogen grouping in linear, branched, or cyclic structuralformats, representative organic groupings being those present in U₁;U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

In some embodiments, the modified alginates are alginate polymers thatcontain one or more covalently modified alginates units described byFormula I, Formula Ia, Formula Ib, combinations of Formula Ia andFormula Ib, Formula II, Formula IIa, Formula IIb, combinations ofFormula IIa and Formula IIb, Formula III, Formula IIIa, Formula IIIb,combinations of Formula IIIa and Formula IIIb, Formula IV, Formula IVa,Formula IVb or combinations of Formula IVa and Formula IVb, wherein foreach formula R₁; R₂, R₃, R₄, R₆, R₇, R₈, and R₉ are independentlyhydrogen or an organic grouping containing any number of carbon atoms,1-30 carbon atoms, 1-20 carbon atoms, or 1-14 carbon atoms, andoptionally including one or more heteroatoms such as oxygen, sulfur, ornitrogen grouping in linear, branched, or cyclic structural formats,representative organic groupings being those present in U₁, U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃; or R₂ and R₃, together with thecarbon atom to which they are attached, form a 3- to 8-memberedunsubstituted or substituted carbocyclic or heterocyclic ring; andwherein R₅ is not hydrogen or an organic grouping containing any numberof carbon atoms, 1-30 carbon atoms, 1-20 carbon atoms, or 1-14 carbonatoms, and optionally including one or more heteroatoms such as oxygen,sulfur, or nitrogen grouping in linear, branched, or cyclic structuralformats, representative organic groupings being those present in U₁;U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

In some embodiments, the modified alginates are alginate polymers thatcontain one or more covalently modified alginates units described byFormula I, Formula Ia, Formula Ib, combinations of Formula Ia andFormula Ib, Formula II, Formula IIa, Formula IIb, combinations ofFormula IIa and Formula IIb, Formula III, Formula IIIa, Formula IIIb,combinations of Formula IIIa and Formula IIIb, Formula IV, Formula IVa,Formula IVb or combinations of Formula IVa and Formula IVb, wherein foreach formula R₁; R₂, R₃, R₄, R₅, R₇, R₈, and R₉ are independentlyhydrogen or an organic grouping containing any number of carbon atoms,1-30 carbon atoms, 1-20 carbon atoms, or 1-14 carbon atoms, andoptionally including one or more heteroatoms such as oxygen, sulfur, ornitrogen grouping in linear, branched, or cyclic structural formats,representative organic groupings being those present in U₁; U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃; or R₂ and R₃, together with thecarbon atom to which they are attached, form a 3- to 8-memberedunsubstituted or substituted carbocyclic or heterocyclic ring; andwherein R₆ is not hydrogen or an organic grouping containing any numberof carbon atoms, 1-30 carbon atoms, 1-20 carbon atoms, or 1-14 carbonatoms, and optionally including one or more heteroatoms such as oxygen,sulfur, or nitrogen grouping in linear, branched, or cyclic structuralformats, representative organic groupings being those present in U₁;U₁+Q₁; U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

In some embodiments, the modified alginates are alginate polymers thatcontain one or more covalently modified alginates units described byFormula I, Formula Ia, Formula Ib, combinations of Formula Ia andFormula Ib, Formula II, Formula IIa, Formula IIb, combinations ofFormula IIa and Formula IIb, Formula III, Formula IIIa, Formula IIIb,combinations of Formula IIIa and Formula IIIb, Formula IV, Formula IVa,Formula IVb or combinations of Formula IVa and Formula IVb, wherein foreach formula R₁; R₂, R₃, R₄, R₅, R₆, R₈, and R₉ are independentlyhydrogen or an organic grouping containing any number of carbon atoms,1-30 carbon atoms, 1-20 carbon atoms, or 1-14 carbon atoms, andoptionally including one or more heteroatoms such as oxygen, sulfur, ornitrogen grouping in linear, branched, or cyclic structural formats,representative organic groupings being those present in U₁; U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃; or R₂ and R₃, together with thecarbon atom to which they are attached, form a 3- to 8-memberedunsubstituted or substituted carbocyclic or heterocyclic ring; andwherein R₇ is not hydrogen or an organic grouping containing any numberof carbon atoms, 1-30 carbon atoms, 1-20 carbon atoms, or 1-14 carbonatoms, and optionally including one or more heteroatoms such as oxygen,sulfur, or nitrogen grouping in linear, branched, or cyclic structuralformats, representative organic groupings being those present in U₁;U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

In some embodiments, the modified alginates are alginate polymers thatcontain one or more covalently modified alginates units described byFormula I, Formula Ia, Formula Ib, combinations of Formula Ia andFormula Ib, Formula II, Formula IIa, Formula IIb, combinations ofFormula IIa and Formula IIb, Formula III, Formula IIIa, Formula IIIb,combinations of Formula IIIa and Formula IIIb, Formula IV, Formula IVa,Formula IVb or combinations of Formula IVa and Formula IVb, wherein foreach formula R₁; R₂, R₃, R₄, R₅, R₆, R₇, and R₉ are independentlyhydrogen or an organic grouping containing any number of carbon atoms,1-30 carbon atoms, 1-20 carbon atoms, or 1-14 carbon atoms, andoptionally including one or more heteroatoms such as oxygen, sulfur, ornitrogen grouping in linear, branched, or cyclic structural formats,representative organic groupings being those present in U₁; U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₄+Q₂+Q₃, U₄+Q₂+Q₄,U₄+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃; or R₂ and R₃, together with thecarbon atom to which they are attached, form a 3- to 8-memberedunsubstituted or substituted carbocyclic or heterocyclic ring; andwherein R₈ is not hydrogen or an organic grouping containing any numberof carbon atoms, 1-30 carbon atoms, 1-20 carbon atoms, or 1-14 carbonatoms, and optionally including one or more heteroatoms such as oxygen,sulfur, or nitrogen grouping in linear, branched, or cyclic structuralformats, representative organic groupings being those present in U₁;U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

In some embodiments, the modified alginates are alginate polymers thatcontain one or more covalently modified alginates units described byFormula I, Formula Ia, Formula Ib, combinations of Formula Ia andFormula Ib, Formula II, Formula IIa, Formula IIb, combinations ofFormula IIa and Formula IIb, Formula III, Formula IIIa, Formula IIIb,combinations of Formula IIIa and Formula IIIb, Formula IV, Formula IVa,Formula IVb or combinations of Formula IVa and Formula IVb, wherein foreach formula R₁; R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are independentlyhydrogen or an organic grouping containing any number of carbon atoms,1-30 carbon atoms, 1-20 carbon atoms, or 1-14 carbon atoms, andoptionally including one or more heteroatoms such as oxygen, sulfur, ornitrogen grouping in linear, branched, or cyclic structural formats,representative organic groupings being those present in U₁; U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃; or R₂ and R₃, together with thecarbon atom to which they are attached, form a 3- to 8-memberedunsubstituted or substituted carbocyclic or heterocyclic ring; andwherein R₉ is not hydrogen or an organic grouping containing any numberof carbon atoms, 1-30 carbon atoms, 1-20 carbon atoms, or 1-14 carbonatoms, and optionally including one or more heteroatoms such as oxygen,sulfur, or nitrogen grouping in linear, branched, or cyclic structuralformats, representative organic groupings being those present in U₁,U₁+Q₁; U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

In some embodiments, the modified alginate polymer is a singularlymodified alginate polymer. In specific embodiments, the singularlymodified alginate polymer contains one or more covalently modifiedmonomers defined by Formula I, Formula Ia, Formula Ib, or combinationsof Formula Ia and Formula Ib, wherein IQ includes an azide group, analkyne group, or a 1,2,3-triazole ring. In certain embodiments, thesingularly modified alginate polymer contains one or more covalentlymodified monomers defined by Formula I, Formula Ia, Formula Ib, orcombinations of Formula Ia and Formula Ib, wherein X is not oxygen andIQ is not an unsubstituted C₁-C₁₈ alkyl group, polyethylene glycol)chain, or cholesteryl moiety. In certain additional embodiments, thesingularly modified alginate polymer contains one or more covalentlymodified monomers defined by Formula I, Formula Ia, Formula Ib, orcombinations of Formula Ia and Formula Ib, wherein X is not NR₄ and R isnot a substituted or unsubstituted C₁-C₆ alkyl group, or a poly(ethyleneglycol) chain.

In alternative embodiments, the modified alginate polymer is a multiplymodified alginate polymer. In preferred embodiments, the multiplymodified alginate polymer possesses a polysaccharide backbone containingmannuronate monomers, guluronate monomers, a first species or type ofcovalently modified monomer defined by Formula I, Formula Ia, FormulaIb, or combinations of Formula Ia and Formula Ib, and a second speciesor type of covalently modified monomer defined by Formula I, Formula Ia,Formula Ib, or combinations of Formula Ia and Formula Ib. In otherembodiments, the multiply modified alginate polymer possesses apolysaccharide backbone containing mannuronate monomers, guluronatemonomers, and three or more different types of covalently modifiedmonomers defined by Formula I, Formula Ia, Formula Ib, or combinationsof Formula Ia and Formula Ib.

In some embodiments, the multiply modified alginate polymer contains twodifferent species of covalently modified monomers defined by Formula I,Formula Ia, Formula Ib, or combinations of Formula Ia and Formula Ib,wherein in both species of monomer, X is NR₄. In other embodiments, themultiply modified alginate polymer contains two different species ofcovalently modified monomers defined by Formula I, Formula Ia, FormulaIb, or combinations of Formula Ia and Formula Ib, wherein in bothspecies of monomer, X is oxygen. In further embodiments, the multiplymodified alginate polymer contains two different species of covalentlymodified monomers defined by Formula I, Formula Ia, Formula Ib, orcombinations of Formula Ia and Formula Ib, wherein in one species ofmonomer X is oxygen, and in the second species of monomer, X is NR₄.

In some embodiments, the multiply modified alginate polymer contains twodifferent species of covalently modified monomers defined by Formula I,Formula Ia, Formula Ib, or combinations of Formula Ia and Formula Ib,wherein in at least one species of monomer, R₄ includes one or morecyclic moieties. In preferred embodiments, the multiply modifiedalginate polymer contains two different species of covalently modifiedmonomers defined by Formula I, Formula Ia, Formula Ib, or combinationsof Formula Ia and Formula Ib, wherein in at least one species ofmonomer, R₄ includes a phenyl ring, furan ring, oxolane ring, dioxolanering, or a 1,2,3-triazole ring.

In certain embodiments, the multiply modified alginate polymer containstwo different species of covalently modified monomers defined by FormulaI, Formula Ia, Formula Ib, or combinations of Formula Ia and Formula Ib,wherein in at least one species of monomer, R₄ includes one or morehalogen moieties, an azide group, or an alkyne.

In preferred embodiments, the multiply modified alginate polymer is oneof the multiply modified alginate polymers shown below.

In some embodiments, R₁ through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently hydrogen, amino, hydroxyl,thiol, oxo, phosphate, or J₁.

In some embodiments, R through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently hydrogen, amino, hydroxyl,thiol, oxo, phosphate, or substituted or unsubstituted C₁-C₁₀ alkyl,C₁-C₁₀ alkoxy, C₁-C₁₀ alkylamino, C₁-C₁₀ alkylthio, C₁-C₉ alkyl, C₁-C₉alkoxy, C₁-C₉ alkylamino, C₁-C₉ alkylthio, C₁-C₈ alkyl, C₁-C₈ alkoxy,C₁-C₈ alkylamino, C₁-C₈alkylthio, C₁-C₇ alkyl, C₁-C₇ alkoxy, C₁-C₇alkylamino, C₁-C₇ alkylthio, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆alkylamino, C₁-C₆ alkylthio, C₁-C₅ alkyl, Cr C₅ alkoxy, C₁-C₅alkylamino, C₁-C₅ alkylthio, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄alkylamino, C₁-C₄ alkylthio, C₁-C₃ alkyl, C₁-C₃ alkoxy, C₁-C₃alkylamino, C₁-C₃ alkylthio, C₁-C₂ alkyl, C₁-C₂ alkoxy, C₁-C₂alkylamino, C₁-C₂ alkylthio, C₁₀ alkyl, C₁₀ alkoxy, C₁₀ alkylamino, C₁₀alkylthio, C₉ alkyl, C₉ alkoxy, C₉ alkylamino, C₉ alkylthio, C₈ alkyl,C₈ alkoxy, C₈ alkylamino, C₈ alkylthio, C₇ alkyl, C₇ alkoxy, C₇alkylamino, C₇ alkylthio, C₆ alkyl, C₆ alkoxy, C₆ alkylamino, C₆alkylthio, C₅ alkyl, C₅ alkoxy, C₅ alkylamino, C₅ alkylthio, C₄ alkyl,C₄ alkoxy, C₄ alkylamino, C₄ alkylthio, C₃ alkyl, C₃ alkoxy, C₃alkylamino, C₃ alkylthio, C₂ alkyl, C₂ alkoxy, C₂ alkylamino, C₂alkylthio, C₁ alkyl, C₄ alkoxy, C₄ alkylamino, or C₄ alkylthio.

In some embodiments, R through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently hydrogen, amino, hydroxyl,thiol, oxo, phosphate, or substituted or unsubstituted C₁-C₁₀ alkyl,C₁-C₁₀ alkoxy, C₁-C₁₀ alkylamino, or C₁-C₁₀ alkylthio.

In some embodiments, R through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently hydrogen, amino, hydroxyl,thiol, oxo, phosphate, or substituted or unsubstituted C₁-C₉ alkyl,C₁-C₉ alkoxy, C₁-C₉ alkylamino, or C₁-C₉ alkylthio.

In some embodiments, R₁ through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently hydrogen, amino, hydroxyl,thiol, oxo, phosphate, or substituted or unsubstituted C₁-C₈ alkyl,C₁-C₈ alkoxy, C₁-C₈ alkylamino, or C₁-C₈ alkylthio.

In some embodiments, R₁ through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently hydrogen, amino, hydroxyl,thiol, oxo, phosphate, or substituted or unsubstituted C₁-C₇ alkyl,C₁-C₇ alkoxy, C₁-C₇ alkylamino, or C₁-C₇ alkylthio.

In some embodiments, R₁ through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently hydrogen, amino, hydroxyl,thiol, oxo, phosphate, or substituted or unsubstituted C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ alkylamino, or C₁-C₆ alkylthio.

In some embodiments, R₁ through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), and R^(d) are independently hydrogen, amino, hydroxyl, thiol,oxo, phosphate, or substituted or unsubstituted C₁-C₅ alkyl, C₁-C₅alkoxy, C₁-C₅ alkylamino, or C₁-C₅ alkylthio.

In some embodiments, R through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently hydrogen, amino, hydroxyl,thiol, oxo, phosphate, or substituted or unsubstituted C₁-C₄ alkyl,C₁-C₄ alkoxy, C₁-C₄ alkylamino, or C₁-C₄ alkylthio.

In some embodiments, R through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently hydrogen, amino, hydroxyl,thiol, oxo, phosphate, or substituted or unsubstituted C₁-C₃ alkyl,C₁-C₃ alkoxy, C₁-C₃ alkylamino, or C₁-C₃ alkylthio.

In some embodiments, R₁ through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently hydrogen, amino, hydroxyl,thiol, oxo, phosphate, or substituted or unsubstituted C₁-C₂ alkyl,C₁-C₂ alkoxy, C₁-C₂ alkylamino, or C₁-C₂ alkylthio.

In some embodiments, R through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently hydrogen, amino, hydroxyl,thiol, oxo, phosphate, or substituted or unsubstituted C₁₀ alkyl, C₁₀alkoxy, C₁₀ alkylamino, or C₁₀ alkylthio.

In some embodiments, R through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently hydrogen, amino, hydroxyl,thiol, oxo, phosphate, or substituted or unsubstituted C₉ alkyl, C₀alkoxy, C₀ alkylamino, or C₀ alkylthio.

In some embodiments, R through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently hydrogen, amino, hydroxyl,thiol, oxo, phosphate, or substituted or unsubstituted C₈ alkyl, C₈alkoxy, C₈ alkylamino, or C₈ alkylthio.

In some embodiments, R through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently hydrogen, amino, hydroxyl,thiol, oxo, phosphate, or substituted or unsubstituted C₇ alkyl, C₇alkoxy, C₇ alkylamino, or C₇ alkylthio.

In some embodiments, R₁ through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently hydrogen, amino, hydroxyl,thiol, oxo, phosphate, or substituted or unsubstituted C₆ alkyl, C₆alkoxy, C₆ alkylamino, or C₆ alkylthio.

In some embodiments, R₁ through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently hydrogen, amino, hydroxyl,thiol, oxo, phosphate, or substituted or unsubstituted C₅ alkyl, C₅alkoxy, C₅ alkylamino, or C₅ alkylthio.

In some embodiments, R₁ through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently hydrogen, amino, hydroxyl,thiol, oxo, phosphate, or substituted or unsubstituted C₄ alkyl, C₄alkoxy, C₄ alkylamino, or C₄ alkylthio.

In some embodiments, R₁ through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently hydrogen, amino, hydroxyl,thiol, oxo, phosphate, or substituted or unsubstituted C₃ alkyl, C₃alkoxy, C₃ alkylamino, or C₃ alkylthio.

In some embodiments, R through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently hydrogen, amino, hydroxyl,thiol, oxo, phosphate, or substituted or unsubstituted C₂ alkyl, C₂alkoxy, C₂ alkylamino, or C₂ alkylthio.

In some embodiments, R through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently hydrogen, amino, hydroxyl,thiol, oxo, phosphate, or substituted or unsubstituted C₁ alkyl, C₁alkoxy, C₁ alkylamino, or C₁ alkylthio.

In some embodiments, R₁ through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently amino, hydroxyl, thiol, oxo,phosphate, or h.

In some embodiments, R₁ through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently amino, hydroxyl, thiol, oxo,phosphate, or substituted or unsubstituted Cr C₁₀ alkyl, C₁-C₁₀ alkoxy,C₁-C₁₀ alkylamino, C₁-C₁₀alkylthio, C₁-C₉ alkyl, C₁-C₉ alkoxy, C₁-C₉alkylamino, C₁-C₉ alkylthio, C₁-C₈ alkyl, C₁-C₈ alkoxy, C₁-C₈alkylamino, C₁-C₈ alkylthio, C₁-C₇ alkyl, C₁-C₇ alkoxy, C₁-C₇alkylamino, C₁-C₇ alkylthio, C₁-C₆ alkyl, Cr C₆ alkoxy, C₁-C₆alkylamino, C₁-C₆ alkylthio, C₁-C₅ alkyl, C₁-C₅ alkoxy, C₁-C₅alkylamino, C₁-C₅ alkylthio, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄alkylamino, C₁-C₄ alkylthio, C₁-C₃ alkyl, C₁-C₃ alkoxy, C₁-C₃alkylamino, C₁-C₃ alkylthio, C₁-C₂ alkyl, C₁-C₂ alkoxy, C₁-C₂alkylamino, C₁-C₂ alkylthio, C₁₀ alkyl, C₁₀ alkoxy, C₁₀ alkylamino, C₁₀alkylthio, C₉ alkyl, C₉ alkoxy, C₉ alkylamino, C₉ alkylthio, C₈ alkyl,C₈ alkoxy, C₈ alkylamino, C₈ alkylthio, C₇ alkyl, C₇ alkoxy, C₇alkylamino, C₇ alkylthio, C₆ alkyl, C₆ alkoxy, C₆ alkylamino, C₆alkylthio, C₅ alkyl, C₅ alkoxy, C₅ alkylamino, C₅ alkylthio, C₄ alkyl,C₄ alkoxy, C₄ alkylamino, C₄ alkylthio, C₃ alkyl, C₃ alkoxy, C₃alkylamino, C₃ alkylthio, C₂ alkyl, C₂ alkoxy, C₂ alkylamino, C₂alkylthio, C₁ alkyl, C₁ alkoxy, C₁ alkylamino, or C₁ alkylthio.

In some embodiments, R₁ through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently amino, hydroxyl, thiol, oxo,phosphate, or substituted or unsubstituted C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy,C₁-C₁₀ alkylamino, or C₁-C₁₀ alkylthio.

In some embodiments, R₁ through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently amino, hydroxyl, thiol, oxo,phosphate, or substituted or unsubstituted Cr C₉ alkyl, C₁-C₉ alkoxy,C₁-C₉ alkylamino, or C₁-C₉ alkylthio.

In some embodiments, R₁ through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently amino, hydroxyl, thiol, oxo,phosphate, or substituted or unsubstituted Cr C₈ alkyl, C₁-C₈ alkoxy,C₁-C₈ alkylamino, or C₁-C₈ alkylthio.

In some embodiments, R through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently amino, hydroxyl, thiol, oxo,phosphate, or substituted or unsubstituted C₁-C₇ alkyl, C₁-C₇ alkoxy,C₁-C₇ alkylamino, or C₁-C₇ alkylthio.

In some embodiments, R through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently amino, hydroxyl, thiol, oxo,phosphate, or substituted or unsubstituted Cr C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ alkylamino, or C₁-C₆ alkylthio.

In some embodiments, R₁ through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently amino, hydroxyl, thiol, oxo,phosphate, or substituted or unsubstituted Cr C₅ alkyl, C₁-C₅ alkoxy,C₁-C₅ alkylamino, or C₁-C₅ alkylthio.

In some embodiments, R₁ through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently amino, hydroxyl, thiol, oxo,phosphate, or substituted or unsubstituted Cr C₄ alkyl, C₁-C₄ alkoxy,C₁-C₄ alkylamino, or C₁-C₄ alkylthio.

In some embodiments, R through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently amino, hydroxyl, thiol, oxo,phosphate, or substituted or unsubstituted Cr C₃ alkyl, C₁-C₃ alkoxy,C₁-C₃ alkylamino, or C₁-C₃ alkylthio.

In some embodiments, R through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently amino, hydroxyl, thiol, oxo,phosphate, or substituted or unsubstituted Cr C₂ alkyl, C₁-C₂ alkoxy,C₁-C₂ alkylamino, or C₁-C₂ alkylthio.

In some embodiments, R through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently amino, hydroxyl, thiol, oxo,phosphate, or substituted or unsubstituted C₁₀ alkyl, C₁₀ alkoxy, C₁₀alkylamino, or C₁₀ alkylthio.

In some embodiments, R₁ through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently amino, hydroxyl, thiol, oxo,phosphate, or substituted or unsubstituted C₉ alkyl, C₉ alkoxy, C₉alkylamino, or C₉ alkylthio.

In some embodiments, R₁ through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently amino, hydroxyl, thiol, oxo,phosphate, or substituted or unsubstituted C₈ alkyl, C₈ alkoxy, C₈alkylamino, or C₈ alkylthio.

In some embodiments, R₁ through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently amino, hydroxyl, thiol, oxo,phosphate, or substituted or unsubstituted C₇ alkyl, C₇ alkoxy, C₇alkylamino, or C₇ alkylthio.

In some embodiments, R₁ through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently amino, hydroxyl, thiol, oxo,phosphate, or substituted or unsubstituted C₆ alkyl, C₆ alkoxy, C₆alkylamino, or C₆ alkylthio.

In some embodiments, R through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently amino, hydroxyl, thiol, oxo,phosphate, or substituted or unsubstituted C₅ alkyl, C₅ alkoxy, C₅alkylamino, or C₅ alkylthio.

In some embodiments, R through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently amino, hydroxyl, thiol, oxo,phosphate, or substituted or unsubstituted C₄ alkyl, C₄ alkoxy, C₄alkylamino, or C₄ alkylthio.

In some embodiments, R₁ through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently amino, hydroxyl, thiol, oxo,phosphate, or substituted or unsubstituted C₃ alkyl, C₃ alkoxy, C₃alkylamino, or C₃ alkylthio.

In some embodiments, R through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently amino, hydroxyl, thiol, oxo,phosphate, or substituted or unsubstituted C₂ alkyl, C₂ alkoxy, C₂alkylamino, or C₂ alkylthio.

In some embodiments, R through R₁₇, R₃₁ through R₃₆, R^(a), R^(b),R^(c), R^(d), and R^(e) are independently amino, hydroxyl, thiol, oxo,phosphate, or substituted or unsubstituted C₁ alkyl, C₄ alkoxy, C₄alkylamino, or C₄ alkylthio.

In some embodiments, -A-B(—C)_(δ), —B(—C)_(δ), A, B, C, R₁; R₄, R₆, R₈,R₉, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, R₃₆, R₅₉, Reo, R^(a), R^(e), R^(d), andR^(e) are independently —R_(h)—(R_(g))_(j)—R_(f), wherein R_(h) isabsent, C(R₅₉R₆₀), O, S, SO₂, SO₃, or NR₆₁; wherein each R_(g) isindependently absent (i.e., j is 0), C(R₄₂R₄₃), O, S, SO₂, SO₃, or NR₄₄;and wherein R_(f) is hydrogen, C(R₄₅R₄₆R₄₇), OH, SH, SO₂, SO₃,Si(R₁₀₀R₁₀₁R₁₀₂), or NR₄₈R₄₉R₅₀;

wherein j is an integer from 0 to 30,

wherein R₅₉, R₆₀, R₆₁, R₄₂, R₄₃, and R₄₄ are each independently, asvalency permits, absent, hydrogen, ═O, —OR₅₁, —SR₅₂, —NR₅₃R₅₄R₅₅,—C(R₅₆R₅₇R58), or —R_(hx)—(R_(gx))_(jx)—R_(fx),

wherein R₄₅, R₄₆, R₄₇, R₄₈, R₄₉, R₅₀, R₅₁, R₅₂, R₅₃, R₅₄, R₅₅, R₅₆, R₅₇,and R₅₈ are each independently, as valency permits, absent, hydrogen,fluorine, —OH, ═O, —SH, =NH, —NH₂, —NH₃, —CH₃, or —COOH,

wherein R₁₀₀, R₁₀₁, and R₁₀₂ are each independently alkyl, phenyl, aryl,or C₃-C₂₀ cyclic,

wherein the bond between R_(h) and R_(g), if present, is single, double,or triple depending on the valency, wherein the bond between R_(g) andR_(f), if present, is single, double, or triple depending on thevalency, wherein the bond between each adjacent R_(g) is single, double,or triple depending on the valency, wherein the bond between R_(h) andR_(f), if present, is single, double, or triple depending on thevalency; wherein when R_(h) is O, S, SO₂, or SO₃, the bond between R_(h)and R_(g) is not a double or triple bond; wherein when R_(h) is NR₆₁,the bond between R_(h) and R_(g) is not a triple bond; wherein whenR_(g) is O, S, SO₂, or SO₃, the bond between R_(g) and R_(h) is not adouble or triple bond; wherein when R_(h) is NR₄₄, the bond betweenR_(g) and R_(h) is not a triple bond; wherein when R_(g) is O, S, SO₂,or SO₃, the bond between R_(g) and R_(f) is not a double or triple bond;wherein when R_(g) is NR₄₄, the bond between R_(g) and R_(f) is not atriple bond; wherein when R_(h) is O, R_(g) is not O, S, or NR₄₄, andvice versa; wherein when R_(h) is S, R_(g) is not O, SO₂, SO₃, or NR₄₄,and vice versa; wherein when R_(h) is SO₂, R_(g) is not S, SO₂, or SO₃,and vice versa; wherein when R_(h) is SO₃, R_(g) is not S, SO₂, or SO₃,and vice versa; wherein when R_(h) is NR₆₁, R_(g) is not O, or S, andvice versa; wherein when R_(g) is O, R_(f) is not OH, SH, or NR₄₈R₄₉R₅₀,and vice versa; wherein when R_(g) is S, R_(f) is not OH, SH, SO₂ orNR₄₈R₄₉R₅₀, and vice versa; wherein when R_(g) is SO₂, R_(f) is not SH,SO₂, or SO₃, and vice versa; wherein when R_(g) is SO₃, R_(f) is not SH,SO₂, or SO₃, and vice versa; and wherein when R_(g) is NR₄₄, R_(f) isnot OH, SH, or SO₂, and vice versa;

wherein each R_(hx) is independently absent, C(R_(59x)R_(60x)), O, S,SO₂, SO₃, or NR_(61x): wherein each R_(gx) is independently absent(i.e., jx is 0), C(R_(42x)R_(43x)), O, S, SO₂, SO₃, or NR_(44x); andwherein each R_(fx) is independently hydrogen, C(R_(45x)R_(46x)R_(47x)),OH, SH, SO₂, SO₃, Si(R_(100x)R_(101x)R_(102x)), orNR_(48x)R_(49x)R_(50x);

wherein jx is an integer from 0 to 20,

wherein R_(59x), R_(60x), R_(61x), R_(42x), R_(43x), and R_(44x) areeach independently, as valency permits, absent, hydrogen, ═O, —OR_(51x),—SR_(52x), —NR_(53x)R_(54x)R_(55x), —C(R_(56x)R_(57x)R_(58x)), or—R_(hy)—(R_(gy))_(jy)—R_(fy),

wherein R_(45x), R_(46x), R_(47x), R_(48x), R_(49x), R_(50x), R_(51X),R_(52x), R_(53x), R_(54x), R_(55x), R_(56x), R_(57x), and R_(58x) areeach independently, as valency permits, absent, hydrogen, —OH, ═O, —SH,=NH, —NH₂, —NH₃, —CH₃, or —COOH,

wherein R_(100x), R_(101x), and R_(102x) are each independently alkyl,phenyl, aryl, or C₃-C₂₀ cyclic,

wherein the bond between each R_(hx) and each respective R_(gx), ifpresent, is single, double, or triple depending on the valency, whereinthe bond between each R_(gx) and each respective R_(fx), if present, issingle, double, or triple depending on the valency, wherein the bondbetween each adjacent R_(gx) is single, double, or triple depending onthe valency, wherein the bond between each R_(hx) and each respectiveR_(fx), if present, is single, double, or triple depending on thevalency; wherein when R_(hx) is O, S, SO₂, or SO₃, the bond betweenR_(hx) and R_(gx) is not a double or triple bond; wherein when R_(hx) isNR_(61x). the bond between R_(hx) and R_(gx) is not a triple bond;wherein when R_(gx) is O, S, SO₂, or SO₃, the bond between R_(gx) andR_(hx) is not a double or triple bond; wherein when R_(hx) is NR_(44x),the bond between R_(gx) and R_(hx) is not a triple bond; wherein whenR_(gx) is O, S, SO₂, or SO₃, the bond between R_(gx) and R_(fx) is not adouble or triple bond; wherein when R_(gx) is NR_(44x), the bond betweenR_(gx) and R_(fx) is not a triple bond; wherein when R_(hx) is O, R_(gx)is not O, S, or NR_(44x) and vice versa; wherein when R_(hx) is S,R_(gx) is not O, SO₂, SO₃, or NR_(44x), and vice versa; wherein whenR_(hx) is SO₂, R_(gx) is not S, SO₂, or SO₃, and vice versa; whereinwhen R_(hx) is SO₃, R_(gx) is not S, SO₂, or SO₃, and vice versa;wherein when R_(hx) is NR_(61x), R_(gx) is not O, or S, and vice versa;wherein when R_(gx) is O, R_(fx) is not OH, SH, orNR_(48x)R_(49x)R_(50x), and vice versa; wherein when R_(gx) is S, R_(fx)is not OH, SH, SO₂ or NR_(48x)R_(49x)R_(50x), and vice versa; whereinwhen R_(gx) is SO₂, R_(fx) is not SH, SO₂, or SO₃, and vice versa;wherein when R_(gx) is SO₃, R_(fx) is not SH, SO₂, or SO₃, and viceversa; and wherein when R_(gx) is NR_(44x), R_(fx) is not OH, SH, orSO₂, and vice versa;

wherein each R_(hy) is independently absent, C(R_(59y)R_(60y)), O, S,SO₂, SO₃, or NR_(61y); wherein each R_(gy) is independently absent(i.e., jy is 0), C(R_(42y)R_(43y)), O, S, SO₂, SO₃, or NR_(44y); andwherein each R_(fy) is independently hydrogen, C(R_(45y)R_(46y)R_(47y)),OH, SH, SO₂, SO₃, Si(R_(100y)R_(101y)R_(102y)), orNR_(48y)R_(49y)R_(50y);

wherein jy is an integer from 0 to 10,

wherein R_(59y), R_(60y), R_(61y), R_(42y), R_(43y), and R_(44y) areeach independently, as valency permits, absent, hydrogen, ═O, —OR_(51y),—SR_(52y), —NR_(53y)R_(54y)R_(55y), -C(R_(56y)R_(57y)R_(58y)), or—R_(hz)—(R_(gz))_(jz)—R_(fz),

wherein R_(45y), R_(46y), R_(47y), R_(48y), R_(49y), R_(50y), R_(51y),R_(52y), R_(53y), R_(54y), R_(55y), R_(56y), R_(57y), and R_(58y) areeach independently, as valency permits, absent, hydrogen, —OH, ═O, —SH,=NH, —NH₂, —NH₃, —CH₃, or —COOH,

wherein R_(100y), R_(101y), and R_(102y) are each independently alkyl,phenyl, aryl, or C₃-C₂₀ cyclic,

wherein the bond between each R_(hy) and each respective R_(gy), ifpresent, is single, double, or triple depending on the valency, whereinthe bond between each R_(gy) and each respective R_(fy), if present, issingle, double, or triple depending on the valency, wherein the bondbetween each adjacent R_(gy) is single, double, or triple depending onthe valency, wherein the bond between each R_(hy) and each respectiveR_(fy), if present, is single, double, or triple depending on thevalency; wherein when R_(hy) is O, S, SO₂, or SO₃, the bond betweenR_(hy) and R_(gy) is not a double or triple bond; wherein when R_(hy) isNR_(61y), the bond between R_(hy) and R_(gy) is not a triple bond;wherein when R_(gy) is O, S, SO₂, or SO₃, the bond between R_(gy) andR_(hy) is not a double or triple bond; wherein when R_(hy) is NR_(44y),the bond between R_(gy) and R_(hy) is not a triple bond; wherein whenR_(gy) is O, S, SO₂, or SO₃, the bond between R_(gy) and R_(fy) is not adouble or triple bond; wherein when R_(gy) is NR_(44y), the bond betweenR_(gy) and R_(fy) is not a triple bond; wherein when R_(hy) is O, R_(gy)is not O, S, or NR_(44y), and vice versa; wherein when R_(hy) is S,R_(gy) is not O, SO₂, SO₃, or NR_(44y), and vice versa; wherein whenR_(hy) is SO₂, R_(gy) is not S, SO₂, or SO₃, and vice versa; whereinwhen R_(hy) is SO₃, R_(gy) is not S, SO₂, or SO₃, and vice versa;wherein when R_(hy) is NR_(61y), R_(gy) is not O, or S, and vice versa;wherein when R_(gy) is O, R_(fy) is not OH, SH, orNR_(48y)R_(49y)R_(50y), and vice versa; wherein when R_(gy) is S, R_(fy)is not OH, SH, SO₂ or NR_(48y)R_(49y)R_(50y), and vice versa; whereinwhen R_(gy) is SO₂, R_(fy) is not SH, SO₂, or SO₃, and vice versa;wherein when R_(gy) is SO₃, R_(fy) is not SH, SO₂, or SO₃, and viceversa; and wherein when R_(gy) is NR_(44y), R_(fy) is not OH, SH, orSO₂, and vice versa;

wherein each R_(hz) is independently absent, C(R_(59z)R_(60z)), O, S,SO₂, SO₃, or NR_(61z); wherein each R_(gz) is independently absent(i.e., jz is 0), C(R_(42z)R_(43z)), O, S, SO₂, SO₃, or NR_(44z); andwherein each R_(fz) is independently hydrogen, C(R_(45z)R_(46z)R_(47z)),OH, SH, SO₂, SO₃, Si(R_(100z)R_(101z)R_(102z)), orNR_(48z)R_(49z)R_(50z);

wherein jz is an integer from 0 to 6,

wherein R_(59z), R_(60z), R_(61z), R_(42z), R_(43z), and R_(44z) areeach independently, as valency permits, absent, hydrogen, ═O, —OR_(51z),—SR_(52z), —NR_(53z)R_(54z)R_(55z), or -C(R_(56z)R_(57z)R_(58z)),

wherein R_(45z), R_(46z), R_(47z), R_(48z), R_(49z), R_(50z), R_(51z),R_(52z), R_(53z), R_(54z), R_(55z), R_(56z), R_(57z), and R_(58z) areeach independently, as valency permits, absent, hydrogen, —OH, ═O, —SH,=NH, —NH₂, —NH₃, —CH₃, or —COOH,

wherein R_(100z), R_(101z), and R_(102z) are each independently alkyl,phenyl, aryl, or C₃-C₂₀ cyclic,

wherein the bond between each R_(hz) and each respective R_(gz), ifpresent, is single, double, or triple depending on the valency, whereinthe bond between each R_(gz) and each respective R_(fz), if present, issingle, double, or triple depending on the valency, wherein the bondbetween each adjacent R_(gz) is single, double, or triple depending onthe valency, wherein the bond between each R_(hz) and each respectiveR_(fz), if present, is single, double, or triple depending on thevalency; wherein when R_(hz) is O, S, SO₂, or SO₃, the bond betweenR_(hz) and R_(gz) is not a double or triple bond; wherein when R_(hz) isNR_(61z), the bond between R_(hz) and R_(gz) is not a triple bond;wherein when R_(gz) is O, S, SO₂, or SO₃, the bond between R_(gz) andR_(hz) is not a double or triple bond; wherein when R_(hz) is NR_(44z),the bond between R_(gz) and R_(hz) is not a triple bond; wherein whenR_(gz) is O, S, SO₂, or SO₃, the bond between R_(gz) and R_(fz) is not adouble or triple bond; wherein when R_(gz) is NR_(44z), the bond betweenR_(gz) and R_(fz) is not a triple bond; wherein when R_(hz) is O, R_(gz)is not O, S, or NR_(44z) and vice versa; wherein when R_(hz) is S,R_(gz) is not O, SO₂, SO₃, or NR_(44z), and vice versa; wherein whenR_(hz) is SO₂, R_(gz) is not S, SO₂, or SO₃, and vice versa; whereinwhen R_(hz) is SO₃, R_(gz) is not S, SO₂, or SO₃, and vice versa;wherein when R_(hz) is NR_(61z), R_(gz) is not O, or S, and vice versa;wherein when R_(gz) is O, R_(fz) is not OH, SH, orNR_(48z)R_(49z)R_(50z), and vice versa; wherein when R_(gz) is S, R_(fz)is not OH, SH, SO₂ or NR_(48z)R_(49z)R_(50z), and vice versa; whereinwhen R_(gz) is SO₂, R_(fz) is not SH, SO₂, or SO₃, and vice versa;wherein when R_(gz) is SO₃, R_(fz) is not SH, SO₂, or SO₃, and viceversa; and wherein when R_(gz) is NR_(44z), R_(fz) is not OH, SH, orSO₂, and vice versa.

Independently in some embodiments of j, and independently in combinationwith any embodiments of any other relevant substituent classes, j can bean integer from 1 to 30, 2 to 30, 3 to 30, 4 to 30, 5 to 30, 6 to 30, 7to 30, 8 to 30, 9 to 30, 10 to 30, 11 to 30, 12 to 30, 13 to 30, 14 to30, 15 to 30, 16 to 30, 17 to 30, 18 to 30, 19 to 30, 20 to 30, 21 to30, 22 to 30, 23 to 30, 24 to 30, 25 to 30, 26 to 30, 27 to 30, 28 to30, 29 to 30, 1 to 29, 2 to 29, 3 to 29, 4 to 29, 5 to 29, 6 to 29, 7 to29, 8 to 29, 9 to 29, 10 to 29, 11 to 29, 12 to 29, 13 to 29, 14 to 29,15 to 29, 16 to 29, 17 to 29, 18 to 29, 19 to 29, 20 to 29, 21 to 29, 22to 29, 23 to 29, 24 to 29, 25 to 29, 26 to 29, 27 to 29, 28 to 29, 1 to28, 2 to 28, 3 to 28, 4 to 28, 5 to 28, 6 to 28, 7 to 28, 8 to 28, 9 to28, 10 to 28, 11 to 28, 12 to 28, 13 to 28, 14 to 28, 15 to 28, 16 to28, 17 to 28, 18 to 28, 19 to 28, 20 to 28, 21 to 28, 22 to 28, 23 to28, 24 to 28, 25 to 28, 26 to 28, 27 to 28, 1 to 27, 2 to 27, 3 to 27, 4to 27, 5 to 27, 6 to 27, 7 to 27, 8 to 27, 9 to 27, 10 to 27, 11 to 27,12 to 27, 13 to 27, 14 to 27, 15 to 27, 16 to 27, 17 to 27, 18 to 27, 19to 27, 20 to 27, 21 to 27, 22 to 27, 23 to 27, 24 to 27, 25 to 27, 26 to27, 1 to 26, 2 to 26, 3 to 26, 4 to 26, 5 to 26, 6 to 26, 7 to 26, 8 to26, 9 to 26, to 26, 11 to 26, 12 to 26, 13 to 26, 14 to 26, 15 to 26, 16to 26, 17 to 26, 18 to 26, 19 to 26, 20 to 26, 21 to 26, 22 to 26, 23 to26, 24 to 26, 25 to 26, 1 to 25, 2 to 25, 3 to 25, 4 to 25, 5 to 25, 6to 25, 7 to 25, 8 to 25, 9 to 25, 10 to 25, 11 to 25, 12 to 25, 13 to25, 14 to 25, 15 to 25, 16 to 25, 17 to 25, 18 to 25, 19 to 25, 20 to25, 21 to 25, 22 to 25, 23 to 25, 24 to 25, 1 to 24, 2 to 24, 3 to 24, 4to 24, 5 to 24, 6 to 24, 7 to 24, 8 to 24, 9 to 24, 10 to 24, 11 to 24,12 to 24, 13 to 24, 14 to 24, 15 to 24, 16 to 24, 17 to 24, 18 to 24, 19to 24, 20 to 24, 21 to 24, 22 to 24, 23 to 24, 1 to 23, 2 to 23, 3 to23, 4 to 23, 5 to 23, 6 to 23, 7 to 23, 8 to 23, 9 to 23, 10 to 23, 11to 23, 12 to 23, 13 to 23, 14 to 23, 15 to 23, 16 to 23, 17 to 23, 18 to23, 19 to 23, 20 to 23, 21 to 23, 22 to 23, 1 to 22, 2 to 22, 3 to 22, 4to 22, 5 to 22, 6 to 22, 7 to 22, 8 to 22, 9 to 22, 10 to 22, 11 to 22,12 to 22, 13 to 22, 14 to 22, 15 to 22, 16 to 22, 17 to 22, 18 to 22, 19to 22, 20 to 22, 21 to 22, 1 to 21, 2 to 21, 3 to 21, 4 to 21, 5 to 21,6 to 21, 7 to 21, 8 to 21, 9 to 21, 10 to 21, 11 to 21, 12 to 21, 13 to21, 14 to 21, 15 to 21, 16 to 21, 17 to 21, 18 to 21, 19 to 21, 20 to21, 1 to 20, 2 to 20, 3 to 20, 4 to 20, 5 to 20, 6 to 20, 7 to 20, 8 to20, 9 to 20, 10 to 20, 11 to 20, 12 to 20, 13 to 20, 14 to 20, 15 to 20,16 to 20, 17 to 20, 18 to 20, 19 to 20, 1 to 19, 2 to 19, 3 to 19, 4 to19, 5 to 19, 6 to 19, 7 to 19, 8 to 19, 9 to 19, 10 to 19, 11 to 19, 12to 19, 13 to 19, 14 to 19, 15 to 19, 16 to 19, 17 to 19, 18 to 19, 1 to18, 2 to 18, 3 to 18, 4 to 18, 5 to 18, 6 to 18, 7 to 18, 8 to 18, 9 to18, 10 to 18, 11 to 18, 12 to 18, 13 to 18, 14 to 18, 15 to 18, 16 to18, 17 to 18, 1 to 17, 2 to 17, 3 to 17, 4 to 17, 5 to 17, 6 to 17, 7 to17, 8 to 17, 9 to 17, to 17, 11 to 17, 12 to 17, 13 to 17, 14 to 17, 15to 17, 16 to 17, 1 to 16, 2 to 16, 3 to 16, 4 to 16, 5 to 16, 6 to 16, 7to 16, 8 to 16, 9 to 16, 10 to 16, 11 to 16, 12 to 16, 13 to 16, 14 to16, 15 to 16, 1 to 15, 2 to 15, 3 to 15, 4 to 15, 5 to 15, 6 to 15, 7 to15, 8 to 15, 9 to 15, 10 to 15, 11 to 15, 12 to 15, 13 to 15, 14 to 15,1 to 14, 2 to 14, 3 to 14, 4 to 14, 5 to 14, 6 to 14, 7 to 14, 8 to 14,9 to 14, 10 to 14, 11 to 14, 12 to 14, 13 to 14, 1 to 13, 2 to 13, 3 to13, 4 to 13, 5 to 13, 6 to 13, 7 to 13, 8 to 13, 9 to 13, 10 to 13, 11to 13, 12 to 13, 1 to 12, 2 to 12, 3 to 12, 4 to 12, 5 to 12, 6 to 12, 7to 12, 8 to 12, 9 to 12, 10 to 12, 11 to 12, 1 to 11, 2 to 11, 3 to 11,4 to 11, 5 to 11, 6 to 11, 7 to 11, 8 to 11, 9 to 11, 10 to 11, 1 to 10,2 to 10, 3 to 10, 4 to 10, 5 to 10, 6 to 10, 7 to 10, 8 to 10, 9 to 10,1 to 9, 2 to 9, 3 to 9, 4 to 9, 5 to 9, 6 to 9, 7 to 9, 8 to 9, 1 to 8,2 to 8, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 7 to 8, 1 to 7, 2 to 7, 3 to 7,4 to 7, 5 to 7, 6 to 7, 1 to 6, 2 to 6, 3 to 6, 4 to 6, 5 to 6, 1 to 5,2 to 5, 3 to 5, 4 to 5, 1 to 4, 2 to 4, 3 to 4, 1 to 3, 2 to 3, or 1 to2. In some embodiments, j is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.

Independently in some embodiments of j, and independently in combinationwith any embodiments of any other relevant substituent classes, j can bean integer from 1 to 10, 2 to 10, 3 to 10, 4 to 10, 5 to 10, 6 to 10, 7to 10, 8 to 10, 9 to 10, 1 to 9, 2 to 9, 3 to 9, 4 to 9, 5 to 9, 6 to 9,7 to 9, 8 to 9, 1 to 8, 2 to 8, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 7 to 8,1 to 7, 2 to 7, 3 to 7, 4 to 7, 5 to 7, 6 to 7, 1 to 6, 2 to 6, 3 to 6,4 to 6, 5 to 6, 1 to 5, 2 to 5, 3 to 5, 4 to 5, 1 to 4, 2 to 4, 3 to 4,1 to 3, 2 to 3, or 1 to 2. Independently in some embodiments of j, andindependently in combination with any embodiments of any other relevantsubstituent classes, j can be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

Independently in some embodiments of j, and independently in combinationwith any embodiments of any other relevant substituent classes, j can bean integer from 1 to 5, 2 to 5, 3 to 5, 4 to 5, 1 to 4, 2 to 4, 3 to 4,1 to 3, 2 to 3, or 1 to 2. In preferred embodiments, j is 1, 2, 3, 4, or5.

Independently in some embodiments of jx, and independently incombination with any embodiments of any other relevant substituentclasses, jx can be an integer from 1 to 20, 2 to 20, 3 to 20, 4 to 20, 5to 20, 6 to 20, 7 to 20, 8 to 20, 9 to 20, 10 to 20, 11 to 20, 12 to 20,13 to 20, 14 to 20, 15 to 20, 16 to 20, 17 to 20, 18 to 20, 19 to 20, 1to 19, 2 to 19, 3 to 19, 4 to 19, 5 to 19, 6 to 19, 7 to 19, 8 to 19, 9to 19, 10 to 19, 11 to 19, 12 to 19, 13 to 19, 14 to 19, 15 to 19, 16 to19, 17 to 19, 18 to 19, 1 to 18, 2 to 18, 3 to 18, 4 to 18, 5 to 18, 6to 18, 7 to 18, 8 to 18, 9 to 18, 10 to 18, 11 to 18, 12 to 18, 13 to18, 14 to 18, 15 to 18, 16 to 18, 17 to 18, 1 to 17, 2 to 17, 3 to 17, 4to 17, 5 to 17, 6 to 17, 7 to 17, 8 to 17, 9 to 17, 10 to 17, 11 to 17,12 to 17, 13 to 17, 14 to 17, 15 to 17, 16 to 17, 1 to 16, 2 to 16, 3 to16, 4 to 16, 5 to 16, 6 to 16, 7 to 16, 8 to 16, 9 to 16, 10 to 16, 11to 16, 12 to 16, 13 to 16, 14 to 16, 15 to 16, 1 to 15, 2 to 15, 3 to15, 4 to 15, 5 to 15, 6 to 15, 7 to 15, 8 to 15, 9 to 15, 10 to 15, 11to 15, 12 to 15, 13 to 15, 14 to 15, 1 to 14, 2 to 14, 3 to 14, 4 to 14,5 to 14, 6 to 14, 7 to 14, 8 to 14, 9 to 14, 10 to 14, 11 to 14, 12 to14, 13 to 14, 1 to 13, 2 to 13, 3 to 13, 4 to 13, 5 to 13, 6 to 13, 7 to13, 8 to 13, 9 to 13, 10 to 13, 11 to 13, 12 to 13, 1 to 12, 2 to 12, 3to 12, 4 to 12, 5 to 12, 6 to 12, 7 to 12, 8 to 12, 9 to 12, to 12, 11to 12, 1 to 11, 2 to 11, 3 to 11, 4 to 11, 5 to 11, 6 to 11, 7 to 11, 8to 11, 9 to 11, 10 to 11, 1 to 10, 2 to 10, 3 to 10, 4 to 10, 5 to 10, 6to 10, 7 to 10, 8 to 10, 9 to 10, 1 to 9, 2 to 9, 3 to 9, 4 to 9, 5 to9, 6 to 9, 7 to 9, 8 to 9, 1 to 8, 2 to 8, 3 to 8, 4 to 8, 5 to 8, 6 to8, 7 to 8, 1 to 7, 2 to 7, 3 to 7, 4 to 7, 5 to 7, 6 to 7, 1 to 6, 2 to6, 3 to 6, 4 to 6, 5 to 6, 1 to 5, 2 to 5, 3 to 5, 4 to 5, 1 to 4, 2 to4, 3 to 4, 1 to 3, 2 to 3, or 1 to 2. In some embodiments, jx is 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

Independently in some embodiments of jx, and independently incombination with any embodiments of any other relevant substituentclasses, jx can be an integer from 1 to 10, 2 to 10, 3 to 10, 4 to 10, 5to 10, 6 to 10, 7 to 10, 8 to 10, 9 to 10, 1 to 9, 2 to 9, 3 to 9, 4 to9, 5 to 9, 6 to 9, 7 to 9, 8 to 9, 1 to 8, 2 to 8, 3 to 8, 4 to 8, 5 to8, 6 to 8, 7 to 8, 1 to 7, 2 to 7, 3 to 7, 4 to 7, 5 to 7, 6 to 7, 1 to6, 2 to 6, 3 to 6, 4 to 6, 5 to 6, 1 to 5, 2 to 5, 3 to 5, 4 to 5, 1 to4, 2 to 4, 3 to 4, 1 to 3, 2 to 3, or 1 to 2. Independently in someembodiments of jx, and independently in combination with any embodimentsof any other relevant substituent classes, jx can be 1, 2, 3, 4, 5, 6,7, 8, 9, or 10.

Independently in some embodiments of jx, and independently incombination with any embodiments of any other relevant substituentclasses, jx can be an integer from 1 to 5, 2 to 5, 3 to 5, 4 to 5, 1 to4, 2 to 4, 3 to 4, 1 to 3, 2 to 3, or 1 to 2. In preferred embodiments,jx is 1, 2, 3, 4, or 5.

Independently in some embodiments of jy, and independently incombination with any embodiments of any other relevant substituentclasses, jy can be an integer from 1 to 10, 2 to 10, 3 to 10, 4 to 10, 5to 10, 6 to 10, 7 to 10, 8 to 10, 9 to 10, 1 to 9, 2 to 9, 3 to 9, 4 to9, 5 to 9, 6 to 9, 7 to 9, 8 to 9, 1 to 8, 2 to 8, 3 to 8, 4 to 8, 5 to8, 6 to 8, 7 to 8, 1 to 7, 2 to 7, 3 to 7, 4 to 7, 5 to 7, 6 to 7, 1 to6, 2 to 6, 3 to 6, 4 to 6, 5 to 6, 1 to 5, 2 to 5, 3 to 5, 4 to 5, 1 to4, 2 to 4, 3 to 4, 1 to 3, 2 to 3, or 1 to 2. Independently in someembodiments of jy, and independently in combination with any embodimentsof any other relevant substituent classes, jy can be 1, 2, 3, 4, 5, 6,7, 8, 9, or 10.

Independently in some embodiments of jy, and independently incombination with any embodiments of any other relevant substituentclasses, jy can be an integer from 1 to 5, 2 to 5, 3 to 5, 4 to 5, 1 to4, 2 to 4, 3 to 4, 1 to 3, 2 to 3, or 1 to 2. In preferred embodiments,jy is 1, 2, 3, 4, or 5.

Independently in some embodiments of jz, and independently incombination with any embodiments of any other relevant substituentclasses, jz can be an integer from 1 to 6, 2 to 6, 3 to 6, 4 to 6, 5 to6, 1 to 5, 2 to 5, 3 to 5, 4 to 5, 1 to 4, 2 to 4, 3 to 4, 1 to 3, 2 to3, or 1 to 2. In preferred embodiments, jz is 1, 2, 3, 4, or 5.

N1

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are carbon, y is 1 to 5, atleast one R^(e) is —O—CH₃, and other R^(e) are independently hydrogen,C₁-C₃ alkyl, or C₁-C₃ alkoxy, the ring of Formula IX is aromatic, R₂₄ is—(CR₂₅R₂₅)_(p)—, R₂₅ are independently hydrogen, C₁-C₃ alkyl, or C₁-C₃alkoxy, and p is 1 to 6. In some embodiments, at least two R^(e) are—O—CH₃. In some embodiments, at least three R^(e) are —O—CH₃. In someembodiments, at least four R^(e) are —O—CH₃. In some embodiments, atleast five R^(e) are —O—CH₃. In some embodiments, p is 1. In someembodiments, p is 2, In some embodiments, p is 3. In some embodiments, pis 4. In some embodiments, p is 5. In some embodiments, p is 6. In someembodiments, y is 1 and R^(e) is at position R₁₉, R₂₀, R₂₁, R₂₂, or R₂₃.In some embodiments, y is 2 and R^(e) are at positions R₁₉ and R₂₀, R₁₉and R₂₁, R₁₉ and R₂₂, R₁₉ and R₂₃, R₂₀ and R₂₁, R₂₀ and R₂₂, R₂₀ andR₂₃, R₂₁ and R₂₂, R₂₁ and R₂₃, or R₂₂ and R₂₃. In some embodiments, y is3 and R^(e) are at positions R₁₉, R₂₀, and R₂₁, R₁₉, R₂₀, and R₂₂, R₁₉,R₂₀, and R₂₃, R₁₉, R₂₁, and R₂₂, R₁₉, R₂₁, and R₂₃, R₁₉, R₂₂, and R₂₃,R₂₀, R₂₁, and R₂₂, R₂₀, R₂₁, and R₂₃, R₂₀, R₂₂, and R₂₃, or R₂₁, R₂₂,and R₂₃. In some embodiments, y is 4 and R^(e) are at positions R₁₉,R₂₀, R₂₁, and R₂₂, R₁₉, R₂₀, R₂₁, and R₂₃, R₁₉, R₂₀, R₂₂, and R₂₃, R₁₉,R₂₁, R₂₂, and R₂₃, or R₂₀, R₂₁, R₂₂, and R₂₃. In some embodiments, y is5 and R^(e) are at positions R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃.

Independently in some embodiments of R₁; and independently incombination with any embodiments of any other relevant substituentclasses, R is Formula IX, wherein in Formula IX, R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are carbon, y is 2, R^(e) is —O—CH₃, R^(e) is at positionsR₂₀ and R₂₁, the ring of Formula IX is aromatic, R₂₄ is —(CR₂₅R₂₅)_(p)—,both R₂₅ are hydrogen, and p is 2.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are carbon, y is 2, R^(e) is—O—CH₃, R^(e) is at positions R₂₀ and R₂₁, the ring of Formula IX isaromatic, R₂₄ is —(CR₂₅R₂₅)_(p)—, both R₂₅ are hydrogen, and p is 2.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, if R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are carbon, y is 2, R^(e)is —O—CH₃, R^(e) is at positions R₂₀ and R₂₁, the ring of Formula IX isaromatic, R₂₄ is —(CR₂₅R₂₅)_(p)—, and both R₂₅ are hydrogen, then p isnot 2. Independently in some embodiments of Formula IX, andindependently in combination with any embodiments of any other relevantsubstituent classes, if R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are carbon, yis 2, R^(e) is —O—CH₃, R^(e) is at positions R₂₀ and R₂₁, the ring ofFormula IX is aromatic, R₂₄ is —(CR₂₅R₂₅)_(p)—, and p is 2, then atleast one R₂₅ is not hydrogen. Independently in some embodiments ofFormula IX, and independently in combination with any embodiments of anyother relevant substituent classes, if R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃are carbon, y is 2, R^(e) is —O—CH₃, R^(e) is at positions R₂₀ and R₂₁,R₂₄ is —(CR₂₅R₂₅)_(p)—, both R₂₅ are hydrogen, and p is 2, then the ringof Formula IX is not aromatic. Independently in some embodiments ofFormula IX, and independently in combination with any embodiments of anyother relevant substituent classes, if R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃are carbon, y is 2, R^(e) is —O—CH₃, the ring of Formula IX is aromatic,R₂₄ is —(CR₂₅R₂₅)_(p)—, both R₂₅ are hydrogen, and p is 2, then R^(e) isnot at positions R₂₀ and R₂₁. Independently in some embodiments ofFormula IX, and independently in combination with any embodiments of anyother relevant substituent classes, if R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃are carbon, y is 2, R^(e) is at positions R₂₀ and R₂₁, the ring ofFormula IX is aromatic, R₂₄ is —(CR₂₅R₂₅)_(p)—, both R₂₅ are hydrogen,and p is 2, then at least one R^(e) is not —O—CH₃. Independently in someembodiments of Formula IX, and independently in combination with anyembodiments of any other relevant substituent classes, if R₁₈, R₁₉, R₂₀,R₂₁, R₂₂, and R₂₃ are carbon, R^(e) is —O—CH₃, R^(e) is at positions R₂₀and R₂₁, the ring of Formula IX is aromatic, R₂₄ is —(CR₂₅R₂₅)_(p)—,both R₂₅ are hydrogen, and p is 2, then y is not 2. Independently insome embodiments of Formula IX, and independently in combination withany embodiments of any other relevant substituent classes, if y is 2,R^(e) is —O—CH₃, R^(e) is at positions R₂₀ and R₂₁, the ring of FormulaIX is aromatic, R₂₄ is —(CR₂₅R₂₅)_(p)—, both R₂₅ are hydrogen, and p is2, then at least one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ is not carbonand the rest of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are carbon.

N2

Independently in some embodiments, and independently in combination withany embodiments of any other relevant substituent classes, X is O, S, orNR₄, R₄ is hydrogen, C₁-C_(N) alkyl, or C₁-C_(N) alkoxy, and R isFormula XIV, wherein R₁₉, R₂₀, R₂₁, and R₂₂ are, independently, oxygenor carbon, R₁₈ is carbon, w is 0 to 3, R^(e) are independently hydrogen,C₁-C₃ alkyl, or C₁-C₃ alkoxy, the ring of Formula XIV has zero, one, ortwo double bonds, R₂₄ is —(CR₂₅R₂₅)_(p)—, R₂₅ are independentlyhydrogen, C₁-C₃ alkyl, or C₁-C₃ alkoxy, and p is 1 to 5. In someembodiments, one of R₁₉, R₂₀, R₂₁, and R₂₂ is oxygen. In someembodiments, two of R₁₉, R₂₀, R₂₁, and R₂₂ are oxygen. In someembodiments, three of R₁₉, R₂₀, R₂₁, and R₂₂ are oxygen. In someembodiments, each of R₁₉, R₂₀, R₂₁, and R₂₂ is oxygen. In someembodiments, w is 1 and R^(e) is at position R₁₉, R₂₀, R₂₁, or R₂₂. Insome embodiments, w is 2 and R^(e) are at positions R₁₉ and R₂₀, R₁₉ andR₂₁, R₁₉ and R₂₂, R₂₀ and R₂₁, R₂₀ and R₂₂, or R₂₁ and R₂₂. In someembodiments, w is 3 and R^(e) are at positions R₁₉, R₂₀, and R₂₁, R₁₉,R₂₀, and R₂₂, R₁₉, R₂₁, and R₂₂, or R₂₀, R₂₁, and R₂₂.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, R₁₉, R₂₀, R₂₁, and R₂₂ are, independently, oxygen or carbon,R₁₈ is carbon, w is 0 to 3, R^(e) are independently hydrogen, C₁-C₃alkyl, or C₁-C₃ alkoxy, the ring of Formula XIV has zero, one, or twodouble bonds, R₂₄ is —(CR₂₅R₂₅)_(p)—, R₂₅ are independently hydrogen,C₁-C₃ alkyl, or C₁-C₃ alkoxy, and p is 1 to 5. In some embodiments, oneof R₁₉, R₂₀, R₂₁, and R₂₂ is oxygen. In some embodiments, two of R₁₉,R₂₀, R₂₁, and R₂₂ are oxygen. In some embodiments, three of R₁₉, R₂₀,R₂₁, and R₂₂ are oxygen. In some embodiments, each of R₁₉, R₂₀, R₂₁, andR₂₂ is oxygen. In some embodiments, w is 1 and R^(e) is at position R₁₉,R₂₀, R₂₁, or R₂₂. In some embodiments, w is 2 and R^(e) are at positionsR₁₉ and R₂₀, R₁₉ and R₂₁, R₁₉ and R₂₂, R₂₀ and R₂₁, R₂₀ and R₂₂, or R₂₁and R₂₂. In some embodiments, w is 3 and R^(e) are at positions R₁₉,R₂₀, and R₂₁, R₁₉, R₂₀, and R₂₂, R₁₉, R₂₁, and R₂₂, or R₂₀, R₂₁, andR₂₂.

Independently in some embodiments, and independently in combination withany embodiments of any other relevant substituent classes, X is NR₄, R₄is methyl, and R₁ is Formula XIV, wherein R₁₉ and R₂₂ are oxygen, R₁₈,R₂₀, and R₂₁ are carbon, w is 0, the ring of Formula XIV has no doublebonds, R₂₄ is —(CR₂₅R₂₅)_(p)—, both R₂₅ are hydrogen, and p is 1.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, R₁₉ and R₂₂ are oxygen, R₁₈, R₂₀, and R₂₁ are carbon, w is 0,the ring of Formula XIV has no double bonds, R₂₄ is —(CR₂₅R₂₅)_(p)—,both R₂₅ are hydrogen, and p is 1.

Independently in some embodiments, and independently in combination withany embodiments of any other relevant substituent classes, if X is NR₄,R₄ is methyl, R₁ is Formula XIV, R₁₉ and R₂₂ are oxygen, R₁₈, R₂₀, andR₂₁ are carbon, w is 0, the ring of Formula XIV has no double bonds, R₂₄is —(CR₂₅R₂₅)_(p)—, and both R₂₅ are hydrogen, then p is not 1.Independently in some embodiments, and independently in combination withany embodiments of any other relevant substituent classes, if X is NR₄,R₄ is methyl, R₁ is Formula XIV, R₁₉ and R₂₂ are oxygen, R₁₈, R₂₀, andR₂₁ are carbon, w is 0, the ring of Formula XIV has no double bonds, R₂₄is —(CR₂₅R₂₅)_(p)—, and p is 1, then at least one R₂₅ is not hydrogen.Independently in some embodiments, and independently in combination withany embodiments of any other relevant substituent classes, if X is NR₄,R₄ is methyl, R₁ is Formula XIV, R₁₉ and R₂₂ are oxygen, R₁₈, R₂₀, andR₂₁ are carbon, w is 0, R₂₄ is —(CR₂₅R₂₅)_(p)—, both R₂₅ are hydrogen,and p is 1, then the ring of Formula XIV has at least one double bonds.Independently in some embodiments, and independently in combination withany embodiments of any other relevant substituent classes, if X is NR₄,R₄ is methyl, R₁ is Formula XIV, R₁₉ and R₂₂ are oxygen, R₁₈, R₂₀, andR₂₁ are carbon, the ring of Formula XIV has no double bonds, R₂₄ is—(CR₂₅R₂₅)_(p)—, both R₂₅ are hydrogen, and p is 1, then w is not 0.Independently in some embodiments, and independently in combination withany embodiments of any other relevant substituent classes, if X is NR₄,R₄ is methyl, R₄ is Formula XIV, R₁₉ and R₂₂ are oxygen, R₁₈, R₂₀, andR₂₁ are carbon, w is 0, the ring of Formula XIV has no double bonds, R₂₄is —(CR₂₅R₂₅)_(p)—, both R₂₅ are hydrogen, and p is 1, then at least oneof R₁₈, R₂₀, and R₂₁ is not carbon. Independently in some embodiments,and independently in combination with any embodiments of any otherrelevant substituent classes, if X is NR₄, R₄ is methyl, R₁ is FormulaXIV, R₁₈, R₂₀, and R₂₁ are carbon, w is 0, the ring of Formula XIV hasno double bonds, R₂₄ is —(CR₂₅R₂₅)_(p)—, both R₂₅ are hydrogen, and p is1, then at least one of R₁₉ and R₂₂ is not oxygen. Independently in someembodiments, and independently in combination with any embodiments ofany other relevant substituent classes, if X is NR₄, R₁ is Formula XIV,R₁₉ and R₂₂ are oxygen, R₁₈, R₂₀, and R₂₁ are carbon, w is 0, the ringof Formula XIV has no double bonds, R₂₄ is —(CR₂₅R₂₅)_(p)—, both R₂₅ arehydrogen, and p is 1, then R₄ is not methyl. Independently in someembodiments, and independently in combination with any embodiments ofany other relevant substituent classes, if R₄ is methyl, R₄ is FormulaXIV, wherein R₁₉ and R₂₂ are oxygen, R₁₈, R₂₀, and R₂₁ are carbon, w is0, the ring of Formula XIV has no double bonds, R₂₄ is —(CR₂₅R₂₅)_(p)—,both R₂₅ are hydrogen, and p is 1, then X is not NR₄.

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, if R₁₉ and R₂₂ are oxygen, R₁₈, R₂₀, and R₂₁ are carbon, w is0, the ring of Formula XIV has no double bonds, R₂₄ is —(CR₂₅R₂₅)_(p)—,and both R₂₅ are hydrogen, then p is not 1. Independently in someembodiments of Formula XIV, and independently in combination with anyembodiments of any other relevant substituent classes, if R₁₉ and R₂₂are oxygen, R₁₈, R₂₀, and R₂₁ are carbon, w is 0, the ring of FormulaXIV has no double bonds, R₂₄ is —(CR₂₅R₂₅)_(p)—, and p is 1, then atleast one R₂₅ is not hydrogen. Independently in some embodiments ofFormula XIV, and independently in combination with any embodiments ofany other relevant substituent classes, if R₁₉ and R₂₂ are oxygen, R₁₈,R₂₀, and R₂₁ are carbon, w is 0, R₂₄ is —(CR₂₅R₂₅)_(p)—, both R₂₅ arehydrogen, and p is 1, then the ring of Formula XIV has at least onedouble bonds. Independently in some embodiments of Formula XIV, andindependently in combination with any embodiments of any other relevantsubstituent classes, if R₁₉ and R₂₂ are oxygen, R₁₈, R₂₀, and R₂₁ arecarbon, the ring of Formula XIV has no double bonds, R₂₄ is—(CR₂₅R₂₅)_(p)—, both R₂₅ are hydrogen, and p is 1, then w is not 0.Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, if R₁₉ and R₂₂ are oxygen, R₁₈, R₂₀, and R₂₁ are carbon, w is0, the ring of Formula XIV has no double bonds, R₂₄ is —(CR₂₅R₂₅)_(p)—,both R₂₅ are hydrogen, and p is 1, then at least one of R₁₈, R₂₀, andR₂₁ is not carbon. Independently in some embodiments of Formula XIV, andindependently in combination with any embodiments of any other relevantsubstituent classes, if R₁₈, R₂₀, and R₂₁ are carbon, w is 0, the ringof Formula XIV has no double bonds, R₂₄ is —(CR₂₅R₂₅)_(p)—, both R₂₅ arehydrogen, and p is 1, then at least one of R₁₀ and R₂₂ is not oxygen.

N3

Independently in some embodiments of —R_(h)—(R_(g))_(j)—R_(f), andindependently in combination with any embodiments of any other relevantsubstituent classes, R_(h) is absent, j is 0 to 10, each R_(g) isC(R₄₂R₄₃), and R_(f) is NR₄₈R₄₉R₅₀, wherein R₄₂, R₄₃, R₄₈, and R₄₉ are,independently, hydrogen, C₁-C₃ alkyl, or C₁-C₃ alkoxy, and R₅₀ isabsent. In some embodiments, all but one, all but two, all but three,all but four, all but five, all but six, all but seven, all but eight,all but none, or all but ten of R₄₂ and R₄₃ are hydrogen. In someembodiments, at least one of R₄₂ and R₄₃ is C₁-C₃ alkyl. In someembodiments, both R₄₂ and R₄₃ are C₁-C₃ alkyl. In some embodiments, atleast one of R₄₂ and R₄₃ is —CH₃. In some embodiments, both R₄₂ and R₄₃are —CH₃. In some embodiments R_(h) is absent, j is 3, and each R_(g) isC(R₄₂R₄₃), wherein R₄₂ and R₄₃ are hydrogen. In some embodiments R_(h)is absent, j is 0 to 10, and each R_(g) is C(R₄₂R₄₃), wherein R₄₂ andR₄₃ are hydrogen. In some embodiments j is 0. In some embodiments jis 1. In some embodiment j is 2. In some embodiments j is 3. In someembodiment j is 4. In some embodiments j is 5. In some embodiments j is7. In some embodiment j is 8. In some embodiments j is 9. In someembodiments j is 10.

Independently in some embodiments of R₁; and independently incombination with any embodiments of any other relevant substituentclasses, R₁ is —R_(h)—(R_(g))_(j)—R_(f), R_(h) is absent, j is 3, eachR_(g) is C(R₄₂R₄₃), and R_(f) is NR₄₈R₄₉R₅₀, wherein R₄₈ and R₄₉ are—CH₃, R₅₀ is absent, and R₄₂ and R₄₃ are hydrogen.

Independently in some embodiments of —R_(h)—(R_(g))_(j)—R_(f), andindependently in combination with any embodiments of any other relevantsubstituent classes, R_(h) is absent, j is 3, each R_(g) is C(R₄₂R₄₃),and R_(f) is NR₄₈R₄₉R₅₀, wherein R₄₈ and R₄₉ are —CH₃, R₅₀ is absent,and R₄₂ and R₄₃ are hydrogen.

Independently in some embodiments of —R_(h)—(R_(g))_(j)—R_(f), andindependently in combination with any embodiments of any other relevantsubstituent classes, if R_(h) is absent, j is 3, each R_(g) isC(R₄₂R₄₃), and R_(f) is NR₄₈R₄₉R₅₀, R₄₈ and R₄₉ are —CH₃, and R₅₀ isabsent, then R₄₂ and R₄₃ are not both hydrogen. Independently in someembodiments of —R_(h)—(R_(g))_(j)—R_(f), and independently incombination with any embodiments of any other relevant substituentclasses, R_(h) is absent, j is 3, each R_(g) is C(R₄₂R₄₃), and R_(f) isNR₄₈R₄₉R₅₀, R₅₀ is absent, and R₄₂ and R₄₃ are hydrogen, then R₄₈ andR₄₉ are not both —CH₃. Independently in some embodiments of—R_(h)—(R_(g))_(j)—R_(f), and independently in combination with anyembodiments of any other relevant substituent classes, R_(h) is absent,each R_(g) is C(R₄₂R₄₃), and R_(f) is NR₄₈R₄₉R₅₀, wherein R₄₈ and R₄₉are —CH₃, R₅₀ is absent, and R₄₂ and R₄₃ are hydrogen, then j is not 3.

N4 and N5

Independently in some embodiments, and independently in combination withany embodiments of any other relevant substituent classes, X is NR₄, R₄is methyl, and R is Formula IX, wherein in Formula IX, R₁₈, R₁₉, R₂₀,R₂₁, R₂₂, and R₂₃ are carbon, y is 0 to 5, at least one R^(e) is —O—CH₃,and other R^(e) are independently hydrogen, C₁-C₃ alkyl, or C₁-C₃alkoxy, the ring of Formula IX is aromatic, R₂₄ is —(CR₂₅R₂₅)_(p)—, R₂₅are independently hydrogen, C₁-C₃ alkyl, or C₁-C₃ alkoxy, and p is 1 to6. Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are carbon, y is 0 to 5, atleast one R^(e) is —O—CH₃, and other R^(e) are independently hydrogen,C₁-C₃ alkyl, or C₁-C₃ alkoxy, the ring of Formula IX is aromatic, R₂₄ is—(CR₂₅R₂₅)_(p)—, R₂₅ are independently hydrogen, C₁-C₃ alkyl, or C₁-C₃alkoxy, and p is 1 to 6. In some embodiments, p is 1. In someembodiments, p is 2, In some embodiments, p is 3. In some embodiments, pis 4. In some embodiments, p is 5. In some embodiments, p is 6. In someembodiments, y is 1 and R^(e) is at position R₁₉, R₂₀, R₂₁, R₂₂, or R₂₃.In some embodiments, y is 2 and R^(e) are at positions R₁₉ and R₂₀, R₁₉and R₂₁, R₁₉ and R₂₂, R₁₉ and R₂₃, R₂₀ and R₂₁, R₂₀ and R₂₂, R₂₀ andR₂₃, R₂₁ and R₂₂, R₂₁ and R₂₃, or R₂₂ and R₂₃. In some embodiments, y is3 and R^(e) are at positions R₁₉, R₂₀, and R₂₁, R₁₉, R₂₀, and R₂₂, R₁₉,R₂₀, and R₂₃, R₁₉, R₂₁, and R₂₂, R₁₉, R₂₁, and R₂₃, R₁₉, R₂₂, and R₂₃,R₂₀, R₂₁, and R₂₂, R₂₀, R₂₁, and R₂₃, R₂₀, R₂₂, and R₂₃, or R₂₁, R₂₂,and R₂₃. In some embodiments, y is 4 and R^(e) are at positions R₁₉,R₂₀, R₂₁, and R₂₂, R₁₉, R₂₀, R₂₁, and R₂₃, R₁₉, R₂₀, R₂₂, and R₂₃, R₁₉,R₂₁, R₂₂, and R₂₃, or R₂₀, R₂₁, R₂₂, and R₂₃. In some embodiments, y is5 and R^(e) are at positions R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃.

Independently in some embodiments, and independently in combination withany embodiments of any other relevant substituent classes, X is NR₄, R₄is methyl, and R₁ is Formula IX, wherein in Formula IX, R₁₈, R₁₉, R₂₀,R₂₁, R₂₂, and R₂₃ are carbon, y is 0, the ring of Formula IX isaromatic, R₂₄ is —(CR₂₅R₂₅)_(p)—, both R₂₅ are hydrogen, and p is 1.

Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are carbon, y is 0, the ringof Formula IX is aromatic, R₂₄ is —(CR₂₅R₂₅)_(p)—, both R₂₅ arehydrogen, and p is 1.

Independently in some embodiments, and independently in combination withany embodiments of any other relevant substituent classes, if X is NR₄,R₄ is methyl, R₁ is Formula IX, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ arecarbon, y is 0, the ring of Formula IX is aromatic, R₂₄ is—(CR₂₅R₂₅)_(p)—, and both R₂₅ are hydrogen, then p is not 1.Independently in some embodiments, and independently in combination withany embodiments of any other relevant substituent classes, if X is NR₄,R₄ is methyl, R₁ is Formula IX, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ arecarbon, y is 0, the ring of Formula IX is aromatic, R₂₄ is—(CR₂₅R₂₅)_(p)—, and p is 1, then at least one both R₂₅ is not hydrogen.Independently in some embodiments, and independently in combination withany embodiments of any other relevant substituent classes, if X is NR₄,R₄ is methyl, R₁ is Formula IX, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ arecarbon, y is 0, R₂₄ is —(CR₂₅R₂₅)_(p)—, both R₂₅ are hydrogen, and p is1, then the ring of Formula IX is not aromatic. Independently in someembodiments, and independently in combination with any embodiments ofany other relevant substituent classes, if X is NR₄, R₄ is methyl, R₄ isFormula IX, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are carbon, the ring ofFormula IX is aromatic, R₂₄ is —(CR₂₅R₂₅)_(p)—, both R₂₅ are hydrogen,and p is 1, then y is not 0. Independently in some embodiments, andindependently in combination with any embodiments of any other relevantsubstituent classes, if X is NR₄, R₄ is methyl, R₁ is Formula IX, y is0, the ring of Formula IX is aromatic, R₂₄ is —(CR₂₅R₂₅)_(p)—, both R₂₅are hydrogen, and p is 1, then at least one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,and R₂₃ is not carbon. Independently in some embodiments, andindependently in combination with any embodiments of any other relevantsubstituent classes, if X is NR₄, R₁ is Formula IX, R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are carbon, y is 0, the ring of Formula IX is aromatic, R₂₄is —(CR₂₅R₂₅)_(p)—, both R₂₅ are hydrogen, and p is 1, then R₄ is notmethyl. Independently in some embodiments, and independently incombination with any embodiments of any other relevant substituentclasses, if R₄ is methyl, R₁ is Formula IX, R₁₈, R₁₉, R₂₀, R₂₁. R₂₂, andR₂₃ are carbon, y is 0, the ring of Formula IX is aromatic, R₂₄ is—(CR₂₅R₂₅)_(p)—, both R₂₅ are hydrogen, and p is 1, then X is not NR₄.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, if R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are carbon, y is 0, thering of Formula IX is aromatic, R₂₄ is —(CR₂₅R₂₅)_(p)—, and both R₂₅ arehydrogen, then p is not 1. Independently in some embodiments of FormulaIX, and independently in combination with any embodiments of any otherrelevant substituent classes, if R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ arecarbon, y is 0, the ring of Formula IX is aromatic, R₂₄ is—(CR₂₅R₂₅)_(p)—, and p is 1, then at least one both R₂₅ is not hydrogen.Independently in some embodiments of Formula IX, and independently incombination with any embodiments of any other relevant substituentclasses, if R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are carbon, y is 0, R₂₄ is—(CR₂₅R₂₅)_(p)—, both R₂₅ are hydrogen, and p is 1, then the ring ofFormula IX is not aromatic. Independently in some embodiments of FormulaIX, and independently in combination with any embodiments of any otherrelevant substituent classes, if R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ arecarbon, the ring of Formula IX is aromatic, R₂₄ is —(CR₂₅R₂₅)_(p)—, bothR₂₅ are hydrogen, and p is 1, then y is not 0. Independently in someembodiments of Formula IX, and independently in combination with anyembodiments of any other relevant substituent classes, if y is 0, thering of Formula IX is aromatic, R₂₄ is —(CR₂₅R₂₅)_(p)—, both R₂₅ arehydrogen, and p is 1, then at least one of R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, andR₂₃ is not carbon.

N6

Independently in some embodiments of —R_(h)—(R_(g))_(j)—R_(f), andindependently in combination with any embodiments of any other relevantsubstituent classes, R_(h) is C(R₅₉R₆₀), j is 2 to 32, and R_(f) isC(R₄₅R₄₆R₄₇), and every other, every third, or every fourth R_(g), ifpresent, is O, wherein every other R_(g), is C(R₄₂R₄₃), wherein R₅₉,R₆₀, R₄₂, and R₄₃ are independently hydrogen, C₁-C₃ alkyl, or C₁-C₃alkoxy, wherein R₄₅, R₄₆, R₄₇, R₄₈, R₄₉, and R₅₀ are independently, asvalency permits, absent, hydrogen, —OH, ═O, —SH, ═N, —NH₂, —NH₃, —CH₃,or —COOH, and wherein R₁₀₀, R₁₀₁, and R₁₀₂ are each independently alkyl,phenyl, aryl, or C₃-C₂₀ cyclic. In some embodiments, R₁₀₀, R₁₀₁, andR₁₀₂ are each independently C₁-C₆alkyl, phenyl, aryl, or C₅-C₆ cyclic.

Independently in some embodiments of —R_(h)—(R_(g))_(j)—R_(f), andindependently in combination with any embodiments of any other relevantsubstituent classes, R_(h) is C(R₅₉R₆₀), and j is 5, 8, 11, 14, 17, 20,23, 26, 29, or 32, wherein the first, third, fourth, sixth, seventh,ninth, tenth, twelfth, thirteenth, fifteenth, sixteenth, eighteenth,nineteenth, twenty-first, twenty-second, twenty-fourth, twenty-fifth,twenty-seventh, twenty-eighth, thirtieth, and thirty-first R_(g), ifpresent, are C(R₄₂R₄₃) and the second, fifth, eighth, eleventh,fourteenth, seventeenth, twentieth, twenty-third, twenty-sixth,twenty-ninth, and thirty-second R_(g), if present, are O, wherein R₅₉,R₆₀, R₄₂, and R₄₃ are independently hydrogen, C₁-C₃ alkyl, or C₁-C₃alkoxy.

Independently in some embodiments of —R_(h)—(R_(g))_(j)—R_(f), andindependently in combination with any embodiments of any other relevantsubstituent classes, R_(h) is C(R₅₉R₆₀), j is 5, 8, 11, 14, 17, 20, 23,26, 29, or 32, and R_(f) is C(R₄₅R₄₆R₄₇), wherein the first, third,fourth, sixth, seventh, ninth, tenth, twelfth, thirteenth, fifteenth,sixteenth, eighteenth, nineteenth, twenty-first, twenty-second,twenty-fourth, twenty-fifth, twenty-seventh, twenty-eighth, thirtieth,and thirty-first R_(g), if present, are C(R₄₂R₄₃) and the second, fifth,eighth, eleventh, fourteenth, seventeenth, twentieth, twenty-third,twenty-sixth, twenty-ninth, and thirty-second R_(g), if present, are O,wherein R₅₉, R₆₀, R₄₂, R₄₃, R₄₅, R₄₆, and R₄₇ are independentlyhydrogen, C₁-C₃ alkyl, or C₁-C₃ alkoxy, wherein R₄₅, R₄₆, R₄₇, R₄₈, R₄₉,and R₅₀ are independently, as valency permits, absent, hydrogen, —OH,═O, —SH, ═N, —NH₂, —NH₃, —CH₃, or —COOH, and wherein R₁₀₀, R₁₀₁, andR₁₀₂ are each independently alkyl, phenyl, aryl, or C₃-C₂₀ cyclic. Insome embodiments, R₁₀₀, R₁₀₁, and R₁₀₂ are each independently G-G,alkyl, phenyl, aryl, or C₅-C₆ cyclic.

Independently in some embodiments of —R_(h)—(R_(g))_(j)—R_(f), andindependently in combination with any embodiments of any other relevantsubstituent classes, R_(h) is C(R₅₉R₆₀), and j is 11, wherein the first,third, fourth, sixth, seventh, ninth, and tenth R_(g) are C(R₄₂R₄₃) andthe second, fifth, eighth, and eleventh R_(g) are O, wherein R₅₉, R₆₀,R₄₂, and R₄₃ are independently hydrogen, C₁-C₃ alkyl, or C₁-C₃ alkoxy.

Independently in some embodiments of —R_(h)—(R_(g))_(j)—R_(f), andindependently in combination with any embodiments of any other relevantsubstituent classes, R_(h) is C(R₅₉R₆₀), j is 11, and R_(f) is hydrogen,C(R₄₅R₄₆R₄₇), OH, SH, S(O)₂, S(O)₃, Si(R₁₀₀R₁₀₁R₁₀₂), or NR₄₈R₄₉R₅₀,wherein the first, third, fourth, sixth, seventh, ninth, and tenth R_(g)are C(R₄₂R₄₃) and the second, fifth, eighth, and eleventh R_(g) are O,wherein R₅₉, R₆₀, R₄₂, and R₄₃ are independently hydrogen, C₁-C₃ alkyl,or C₁-C₃ alkoxy, wherein R₄₅, R₄₆, R₄₇, R₄₈, R₄₉, and R₅₀ areindependently, as valency permits, absent, hydrogen, —OH, ═O, —SH, ═N,—NH₂, —NH₃, —CH₃, or —COOH, and wherein R₁₀₀, R₁₀₁, and R₁₀₂ are eachindependently alkyl, phenyl, aryl, or C₃-C₂₀ cyclic. In someembodiments, R₁₀₀, R₁₀₁, and R₁₀₂ are each independently G-G, alkyl,phenyl, aryl, or C₅-C₆ cyclic.

Independently in some embodiments of —R_(h)—(R_(g))_(j)—R_(f), andindependently in combination with any embodiments of any other relevantsubstituent classes, R_(h) is C(R₅₉R₆₀), and j is 5, 8, 11, 14, 17, 20,23, 26, 29, or 32, wherein the first, third, fourth, sixth, seventh,ninth, tenth, twelfth, thirteenth, fifteenth, sixteenth, eighteenth,nineteenth, twenty-first, twenty-second, twenty-fourth, twenty-fifth,twenty-seventh, twenty-eighth, thirtieth, and thirty-first R_(g), ifpresent, are C(R₄₂R₄₃) and the second, fifth, eighth, eleventh,fourteenth, seventeenth, twentieth, twenty-third, twenty-sixth,twenty-ninth, and thirty-second R_(g), if present, are O, wherein R₅₉,R₆₀, R₄₂, and R₄₃ are independently hydrogen, C₁-C₃ alkyl, or C₁-C₃alkoxy.

Independently in some embodiments of —R_(h)—(R_(g))_(j)—R_(f), andindependently in combination with any embodiments of any other relevantsubstituent classes, R_(h) is C(R₅₉R₆₀), j is 5, 8, 11, 14, 17, 20, 23,26, 29, or 32, and R_(f) is hydrogen, C(R₄₅R₄₆R₄₇), OH, SH, S(O)₂,S(O)₃, Si(R₁₀₀R₁₀₁R₁₀₂), or NR₄₈R₄₉R₅₀, wherein the first, third,fourth, sixth, seventh, ninth, tenth, twelfth, thirteenth, fifteenth,sixteenth, eighteenth, nineteenth, twenty-first, twenty-second,twenty-fourth, twenty-fifth, twenty-seventh, twenty-eighth, thirtieth,and thirty-first R_(g), if present, are C(R₄₂R₄₃) and the second, fifth,eighth, eleventh, fourteenth, seventeenth, twentieth, twenty-third,twenty-sixth, twenty-ninth, and thirty-second R_(g), if present, are O,wherein R₅₉, R₆₀, R₄₂, and R₄₃ are hydrogen, wherein R₄₅, R₄₆, R₄₇, R₄₈,R₄₉, and R₅₀ are independently, as valency permits, absent, hydrogen,—OH, ═O, —SH, ═N, —NH₂, —NH₃, —CH₃, or —COOH, and wherein R₁₀₀, R₁₀₁,and R₁₀₂ are each independently alkyl, phenyl, aryl, or C₃-C₂₀ cyclic.In some embodiments, R₁₀₀, R₁₀₁, and R₁₀₂ are each independently C₁-C₆alkyl, phenyl, aryl, or C₅-C₆ cyclic.

Independently in some embodiments of —R_(h)—(R_(g))_(j)—R_(f), andindependently in combination with any embodiments of any other relevantsubstituent classes, R_(h) is C(R₅₉R₆₀), and j is 11, wherein the first,third, fourth, sixth, seventh, ninth, and tenth R_(g) are C(R₄₂R₄₃) andthe second, fifth, eighth, and eleventh R_(g) are O, wherein R₅₉, R₆₀,R₄₂, and R₄₃ are hydrogen.

Independently in some embodiments of R₁; and independently incombination with any embodiments of any other relevant substituentclasses, R₁ is —R_(h)—(R_(g))_(j)—R_(f), R_(h) is C(R₅₉R₆₀), j is 11,and R_(f) is C(R₄₅R₄₆R₄₇), wherein the first, third, fourth, sixth,seventh, ninth, and tenth R_(g) are C(R₄₂R₄₃) and the second, fifth,eighth, and eleventh R_(g) are O, wherein R₅₉, R₆₀, R₄₂, R₄₃, R₄₅, R₄₆,and R₄₇ are hydrogen.

Independently in some embodiments of —R_(h)—(R_(g))_(j)—R_(f), andindependently in combination with any embodiments of any other relevantsubstituent classes, R_(h) is C(R₅₉R₆₀), j is 11, and R_(f) isC(R₄₅R₄₆R₄₇), wherein the first, third, fourth, sixth, seventh, ninth,and tenth R_(g) are C(R₄₂R₄₃) and the second, fifth, eighth, andeleventh R_(g) are O, wherein R₅₉, R₆₀, R₄₂, R₄₃, R₄₅, R₄₆, and R₄₃ arehydrogen.

Independently in some embodiments of —R_(h)—(R_(g))_(j)—R_(f), andindependently in combination with any embodiments of any other relevantsubstituent classes, if R_(h) is C(R₅₉R₆₀), j is 11, R_(f) isC(R₄₅R₄₆R₄₇), the first, third, fourth, sixth, seventh, ninth, and tenthR_(g) are C(R₄₂R₄₃), the second, fifth, eighth, and eleventh R_(g) areO, then at least one of R₅₉, R₆₀, R₄₂, R₄₃, R₄₅, R₄₆, and R₄₇ is nothydrogen. Independently in some embodiments of —R_(h)—(R_(g))_(j)—R_(f),and independently in combination with any embodiments of any otherrelevant substituent classes, if R_(h) is C(R₅₉R₆₀), j is 11, R_(f) isC(R₄₅R₄₆R₄₇), the first, third, fourth, sixth, seventh, ninth, and tenthR_(g) are C(R₄₂R₄₃), and R₅₀, R₆₀, R₄₂, R₄₃, R₄₅, R₄₆, and R₄₇ arehydrogen, then at least one of the second, fifth, eighth, and eleventhR_(g) is not O. Independently in some embodiments of—R_(h)—(R_(g))_(j)—R_(f), and independently in combination with anyembodiments of any other relevant substituent classes, if R_(h) isC(R₅₉R₆₀), j is 11, R_(f) is C(R₄₅R₄₆R₄₇), the second, fifth, eighth,and eleventh R_(g) are O, and R₅₉, R₆₀, R₄₂, R₄₃, R₄₅, R₄₆, and R₄₇ arehydrogen, then at least one of the first, third, fourth, sixth, seventh,ninth, and tenth R_(g) is not C(R₄₂R₄₃). Independently in someembodiments of —R_(h)—(R_(g))_(j)—R_(f), and independently incombination with any embodiments of any other relevant substituentclasses, if R_(h) is C(R₅₉R₆₀), R_(f) is C(R₄₅R₄₆R₄₇), the first, third,fourth, sixth, seventh, ninth, and tenth R_(g) are C(R₄₂R₄₃), thesecond, fifth, eighth, and eleventh R_(g) are O, and R₅₉, R₆₀, R₄₂, R₄₃,R₄₅, R₄₆, and R₄₇ are hydrogen, them j is not 11.

N7

Independently in some embodiments, and independently in combination withany embodiments of any other relevant substituent classes, X is O, S, orNR₄, R₄ is hydrogen, C₁-C₃ alkyl, or C₁-C₃ alkoxy, R₄ is—R_(h)—(R_(g))_(j)—R_(f), R_(h) is absent, C(R₅₉R₆₀), O, S, S(O)₂,S(O)₃, or NR₆₁, j is 0 to 12, each R_(g) is C(R₄₂R₄₃), R_(f) ishydrogen, C(R₄₅R₄₆R₄₇), OH, SH, or NR₄₈R₄₉R₅₀, R₅₉, R₆₀, R₆₁, R₄₂, R₄₃,R₄₅, R₄₆, R₄₈, R₄₉, R₄₈, and R₄₃ are independently hydrogen, C₁-C₃alkyl, or C₁-C₃ alkoxy, R₄₇ and R₅₀ are independently absent, hydrogen,C₁-C₃ alkyl, or C₁-C₃ alkoxy. Independently in some embodiments of—R_(h)—(R_(g))_(j)—R_(f), and independently in combination with anyembodiments of any other relevant substituent classes, R_(h) is absent,C(R₅₉R₆₀), O, S, S(O)₂, S(O)₃, or NR₆₁, j is 0 to 12, each R_(g) isC(R₄₂R₄₃), R_(f) is hydrogen, C(R₄₅R₄₆R₄₇), OH, SH, or NR₄₈R₄₉R₅₀, R₅₉,R₆₀, R₆₁, R₄₂, R₄₃, R₄₅, R₄₆, R₄₈, R₄₉, R₄₈, and R₄₉ are independentlyhydrogen, C₁-C₃ alkyl, or C₁-C₃ alkoxy, R₄₇ and R₅₀ are independentlyabsent, hydrogen, C₁-C₃ alkyl, or C₁-C₃ alkoxy. In some embodiments, Xis O. In some embodiments, X is S. In some embodiments, X is NR₄, R₄ ishydrogen, C₁-C₃ alkyl, or C₁-C₃ alkoxy. In some embodiments, R₄ ishydrogen. In some embodiments, R₄ is C₁-C₃ alkyl. In some embodiments,R₄ is C₁-C₃ alkoxy. In some embodiments, R₄ is methyl. In someembodiments, R₄ is —O—CH₃. In some embodiments, R_(h) is absent. In someembodiments, R_(h) is C(R₅₉R₆₀). In some embodiments, R_(h) is O. Insome embodiments, R_(h) is S. In some embodiments, R_(h) is S(O)₂. Insome embodiments, R_(h) is S(O)₃. In some embodiments, R_(h) is NR₆₁. Insome embodiments, at least one R₄₂ or R₄₃ is not hydrogen. In someembodiments, at least one R₄₈ or R₄₉ is not hydrogen. In someembodiments j is 0. In some embodiments j is 1. In some embodiment j is2. In some embodiments j is 3. In some embodiment j is 4. In someembodiments j is 5. In some embodiments j is 7. In some embodiment j is8. In some embodiments j is 9. In some embodiments j is 10. In someembodiments j is 11. In some embodiments j is 12. In some embodiments R₄is hydrogen, methyl, ethyl, or butyl.

Independently in some embodiments, and independently in combination withany embodiments of any other relevant substituent classes, X is NR₄, R₄is methyl, R₁ is —R_(h)—(R_(g))_(j)—R_(f), R_(h) is absent, j is 6,R_(g) are C(R₄₂R₄₃), R_(f) is NR₄₈R₄₉R₅₀, R₄₈ is —CH₃, R₄₂, R₄₃, and R₄₉are hydrogen, R₅₀ is absent.

Independently in some embodiments of —R_(h)—(R_(g))_(j)—R_(f), andindependently in combination with any embodiments of any other relevantsubstituent classes, R_(h) is absent, j is 6, R_(g) are C(R₄₂R₄₃), R_(f)is NR₄₈R₄₉R₅₀, R₄₈ is —CH₃, R₄₂, R₄₃, and R₄₉ are hydrogen, R₅₀ isabsent.

Independently in some embodiments, and independently in combination withany embodiments of any other relevant substituent classes, if X is NR₄,R₄ is methyl, R₁ is —R_(h)—(R_(g))_(j)—R_(f), R_(h) is absent, j is 6,R_(g) are C(R₄₂R₄₃), R_(f) is NR₄₈R₄₉R₅₀, R₄₈ is —CH₃, and R₄₂, R₄₃, andR₄₃ are hydrogen, then R₅₀ is present. Independently in someembodiments, and independently in combination with any embodiments ofany other relevant substituent classes, if X is NR₄, R₄ is methyl, R₁ is—R_(h)—(R_(g))_(j)—R_(f), R_(h) is absent, j is 6, R_(g) are C(R₄₂R₄₃),R_(f) is NR₄₈R₄₉R₅₀, R₄₃ is —CH₃, and R₅₀ is absent, then at least oneof R₄₂, R₄₃, and R₄₉ is not hydrogen. Independently in some embodiments,and independently in combination with any embodiments of any otherrelevant substituent classes, if X is NR₄, R₄ is methyl, R₁ is—R_(h)—(R_(g))_(j)—R_(f), R_(h) is absent, j is 6, R_(g) are C(R₄₂R₄₃),R_(f) is NR₄₈R₄₉R₅₀, R₄₂, R₄₃, and R₄₉ are hydrogen, and R₅₀ is absent,then R₄₈ is not —CH₃. Independently in some embodiments, andindependently in combination with any embodiments of any other relevantsubstituent classes, if X is NR₄, R₄ is methyl, R₄ is—R_(h)—(R_(g))_(j)—R_(f), R_(h) is absent, j is 6, R_(g) are C(R₄₂R₄₃),R₄₈ is —CH₃, R₄₂, R₄₃, and R₄₉ are hydrogen, and R₅₀ is absent, thenR_(f) is not NR₄₈R₄₉R₅₀. Independently in some embodiments, andindependently in combination with any embodiments of any other relevantsubstituent classes, if X is NR₄, R₄ is methyl, R₁ is—R_(h)—(R_(g))_(j)—R_(f), R_(h) is absent, j is 6, R_(f) is NR₄₈R₄₉R₅₀,R₄₈ is —CH₃, R₄₂, R₄₃, and R₄₉ are hydrogen, and R₅₀ is absent, then atleast one R_(g) is not C(R₄₂R₄₃). Independently in some embodiments, andindependently in combination with any embodiments of any other relevantsubstituent classes, if X is NR₄, R₄ is methyl, R₁ is—R_(h)—(R_(g))_(j)—R_(f), R_(h) is absent, R_(g) are C(R₄₂R₄₃), R_(f) isNR₄₈R₄₉R₅₀, R₄₃ is —CH₃, R₄₂, R₄₃, and R₄₉ are hydrogen, and R₅₀ isabsent, then j is not 6. Independently in some embodiments, andindependently in combination with any embodiments of any other relevantsubstituent classes, if X is NR₄, R₄ is methyl, R₁ is—R_(h)—(R_(g))_(j)—R_(f), j is 6, R_(g) are C(R₄₂R₄₃), R_(f) isNR₄₈R₄₉R₅₀, R₄₈ is —CH₃, R₄₂, R₄₃, and R₄₉ are hydrogen, and R₅₀ isabsent, then R_(h) is present. Independently in some embodiments, andindependently in combination with any embodiments of any other relevantsubstituent classes, if X is NR₄, R₁ is —R_(h)—(R_(g))_(j)—R_(f), R_(h)is absent, j is 6, R_(g) are C(R₄₂R₄₃), R_(f) is NR₄₈R₄₉R₅₀, R₄₈ is—CH₃, R₄₂, R₄₃, and R₄₃ are hydrogen, and R₅₀ is absent, then R₄ is notmethyl. Independently in some embodiments of R₁; and independently incombination with any embodiments of any other relevant substituentclasses, if R₄ is —R_(h)—(R_(g))_(j)—R_(f), R_(h) is absent, j is 6,R_(g) are C(R₄₂R₄₃), R_(f) is NR₄₈R₄₉R₅₀, R₄₃ is —CH₃, R₄₂, R₄₃, and R₄₉are hydrogen, and R₅₀ is absent, then X is not NR₄. Independently insome embodiments of —R_(h)—(R_(g))_(j)—R_(f), and independently incombination with any embodiments of any other relevant substituentclasses, if R_(h) is absent, j is 6, R_(g) are C(R₄₂R₄₃), R_(f) isNR₄₈R₄₉R₅₀, R₄₈ is —CH₃, and R₄₂, R₄₃, and R₄₉ are hydrogen, then R₅₀ ispresent. Independently in some embodiments of —R_(h)—(R_(g))_(j)—R_(f),and independently in combination with any embodiments of any otherrelevant substituent classes, if R_(h) is absent, j is 6, R_(g) areC(R₄₂R₄₃), R_(f) is NR₄₈R₄₉R₅₀, R₄₈ is —CH₃, and R₅₀ is absent, then atleast one of R₄₂, R₄₃, and R₄₉ is not hydrogen. Independently in someembodiments of —R_(h)—(R_(g))_(j)—R_(f), and independently incombination with any embodiments of any other relevant substituentclasses, if R_(h) is absent, j is 6, R_(g) are C(R₄₂R₄₃), R_(f) isNR₄₈R₄₉R₅₀, R₄₂, R₄₃, and R₄₃ are hydrogen, and R₅₀ is absent, then R₄₈is not —CH₃. Independently in some embodiments of—R_(h)—(R_(g))_(j)—R_(f), and independently in combination with anyembodiments of any other relevant substituent classes, if R_(h) isabsent, j is 6, R_(g) are C(R₄₂R₄₃), R₄₈ is —CH₃, R₄₂, R₄₃, and R₄₉ arehydrogen, and R₅₀ is absent, then R_(f) is not NR₄₈R₄₉R₅₀. Independentlyin some embodiments of —R_(h)—(R_(g))_(j)—R_(f), and independently incombination with any embodiments of any other relevant substituentclasses, if R_(h) is absent, j is 6, R_(f) is NR₄₈R₄₉R₅₀, R₄₈ is —CH₃,R₄₂, R₄₃, and R₁₉ are hydrogen, and R₅₀ is absent, then at least oneR_(g) is not C(R₄₂R₄₃). Independently in some embodiments of—R_(h)—(R_(g))_(j)—R_(f), and independently in combination with anyembodiments of any other relevant substituent classes, if R_(h) isabsent, R_(g) are C(R₄₂R₄₃), R_(f) is NR₄₈R₄₉R₅₀, R₄₈ is —CH₃, R₄₂, R₄₃,and R₄₃ are hydrogen, and R₅₀ is absent, then j is not 6. Independentlyin some embodiments of —R_(h)—(R_(g))_(j)—R_(f), and independently incombination with any embodiments of any other relevant substituentclasses, if j is 6, R_(g) are C(R₄₂R₄₃), R_(f) is NR₄₈R₄₉R₅₀, R₄₈ is—CH₃, R₄₂, R₄₃, and R₄₉ are hydrogen, and R₅₀ is absent, then R_(h) ispresent.

N8

Independently in some embodiments of —R_(h)—(R_(g))_(j)—R_(f), andindependently in combination with any embodiments of any other relevantsubstituent classes, R_(h) is C(R₅₉R₆₀), j is 1, 4, 7, 10, 13, or 16,the first, third, fourth, sixth, seventh, ninth, tenth, twelfth,thirteenth, fifteenth, and sixteenth R_(g), if present, are C(R₄₂R₄₃),and the second, fifth, eighth, eleventh, and fourteenth R_(g), ifpresent, are O, wherein R₅₉, R₆₀, R₄₂, and R₄₃ are hydrogen.

Independently in some embodiments of —R_(h)—(R_(g))_(j)—R_(f), andindependently in combination with any embodiments of any other relevantsubstituent classes, R_(h) is C(R₅₉R₆₀), j is 1, 4, 7, 10, 13, or 16,the first, third, fourth, sixth, seventh, ninth, tenth, twelfth,thirteenth, fifteenth, and sixteenth R_(g), if present, are C(R₄₂R₄₃),the second, fifth, eighth, eleventh, and fourteenth R_(g), if present,are O, and R_(f) is OH, wherein R₅₉, R₆₀, R₄₂, and R₄₃ are hydrogen.

Independently in some embodiments of —R_(h)—(R_(g))_(j)—R_(f), andindependently in combination with any embodiments of any other relevantsubstituent classes, R_(h) is C(R₅₉R₆₀), j is 4 to 16, one R_(g) is O,and the other R_(g) are C(R₄₂R₄₃), wherein R₅₉, R₆₀, R₄₂, and R₄₃ arehydrogen. In some embodiments the first R_(g) is O. In some embodimentsthe second R_(g) is O. In some embodiments the third R_(g) is O. In someembodiments the fourth R_(g) is O. In some embodiments the fifth R_(g)is O. In some embodiments the sixth R_(g) is O.

In some embodiments the fifth from the last R_(g) is O. In someembodiments the fourth from the last R_(g) is O. In some embodiments theantepenultimate R_(g) is O. In some embodiments the penultimate R_(g) isnot O. In some embodiments the last R_(g) is not O. In some embodimentsneither the penultimate R_(g) nor the last R_(g) is O.

Independently in some embodiments of —R_(h)—(R_(g))_(j)—R_(f), andindependently in combination with any embodiments of any other relevantsubstituent classes, R_(h) is C(R₅₉R₆₀), j is 4 to 16, one R_(g) is O,the other R_(g) are C(R₄₂R₄₃), and R_(f) is OH, wherein R₅₉, R₆₀, R₄₂,and R₄₃ are hydrogen. In some embodiments the first R_(g) is O. In someembodiments the second R_(g) is O. In some embodiments the third R_(g)is O. In some embodiments the fourth R_(g) is O. In some embodiments thefifth R_(g) is O. In some embodiments the sixth R_(g) is O. In someembodiments the fifth from the last R_(g) is O. In some embodiments thefourth from the last R_(g) is O. In some embodiments the antepenultimateR_(g) is O. In some embodiments the penultimate R_(g) is not O. In someembodiments the last R_(g) is not O. In some embodiments neither thepenultimate R_(g) nor the last R_(g) is O.

Independently in some embodiments of —R_(h)—(R_(g))_(j)—R_(f), andindependently in combination with any embodiments of any other relevantsubstituent classes, R_(h) is C(R₅₉R₆₀), j is 4, the first, third, andfourth R_(g) are C(R₄₂R₄₃), and the second R_(g) is O, wherein R₅₉, R₆₀,R₄₂, and R₄₃ are hydrogen.

Independently in some embodiments of R₁; and independently incombination with any embodiments of any other relevant substituentclasses, R₁ is —R_(h)—(R_(g))_(j)—R_(f), R_(h) is C(R₅₉R₆₀), j is 4, thefirst, third, and fourth R_(g) are C(R₄₂R₄₃), the second R_(g) is O, andR_(f) is OH, wherein R₅₉, R₆₀, R₄₂, and R₄₃ are hydrogen.

Independently in some embodiments of —R_(h)—(R_(g))_(j)—R_(f), andindependently in combination with any embodiments of any other relevantsubstituent classes, R_(h) is C(R₅₉R₆₀), j is 4, the first, third, andfourth R_(g) are C(R₄₂R₄₃), the second R_(g) is O, and R_(f) is OH,wherein R₅₉, R₆₀, R₄₂, and R₄₃ are hydrogen.

Independently in some embodiments of —R_(h)—(R_(g))_(j)—R_(f), andindependently in combination with any embodiments of any other relevantsubstituent classes, if R_(h) is C(R₅₉R₆₀), j is 4, the first, third,and fourth R_(g) are C(R₄₂R₄₃), the second R_(g) is O, and R_(f) is OH,then at least one of R₅₉, R₆₀, R₄₂, and R₄₃ is not hydrogen.Independently in some embodiments of —R_(h)—(R_(g))_(j)—R_(f), andindependently in combination with any embodiments of any other relevantsubstituent classes, if R_(h) is C(R₅₉R₆₀), j is 4, the first, third,and fourth R_(g) are C(R₄₂R₄₃), the second R_(g) is O, and R₅₉, R₆₀,R₄₂, and R₄₃ are hydrogen, then R_(f) is not OH. Independently in someembodiments of —R_(h)—(R_(g))_(j)—R_(f), and independently incombination with any embodiments of any other relevant substituentclasses, if R_(h) is C(R₅₉R₆₀), j is 4, the first, third, and fourthR_(g) are C(R₄₂R₄₃), R_(f) is OH, and R₅₉, R₆₀, R₄₂, and R₄₃ arehydrogen, then the second R_(g) is not O. Independently in someembodiments of —R_(h)—(R_(g))_(j)—R_(f), and independently incombination with any embodiments of any other relevant substituentclasses, if R_(h) is C(R₅₉R₆₀), j is 4, the second R_(g) is O, R_(f) isOH, and R₅₉, R₆₀, R₄₂, and R₄₃ are hydrogen, then at least one of thefirst, third, and fourth R_(g) is not C(R₄₂R₄₃). Independently in someembodiments of —R_(h)—(R_(g))_(j)—R_(f), and independently incombination with any embodiments of any other relevant substituentclasses, if R_(h) is C(R₅₉R₆₀), the first, third, and fourth R_(g) areC(R₄₂R₄₃), the second R_(g) is O, R_(f) is OH, and R₅₉, R₆₀, R₄₂, andR₄₃ are hydrogen, then j is not 4.

N9

In some embodiments R₄ is methyl, R_(h) is NR₆₁, j is 4, and R_(g) isC(R₄₂R₄₃), wherein NR₆₁ is —R_(hx)—(R_(gx))_(jx)—R_(fx) and R₄₂ and R₄₃are hydrogen, wherein R_(hx) is C(R_(59x)R_(60x)), jx=0, and R_(fx) isC(R_(45x)R_(46x)R_(47x)), and wherein R_(59x), R_(60x), R_(45x),R_(46x), R_(47x) are hydrogen.

In some embodiments R₄ is methyl, R_(h) is NR₆₁, j is 4, R_(g) isC(R₄₂R₄₃), and R_(f) is OH, wherein NR₆₁ is —R_(hx)—(R_(gx))_(jx)—R_(fx)and R₄₂ and R₄₃ are hydrogen, wherein R_(hx) is C(R_(59x)R_(60x)), jx=0,and R_(fx) is C(R_(45x)R_(46x)R_(47x)), and wherein R_(59x), R_(60x),R_(45x), R_(46x), R_(47x) are hydrogen.

In some embodiments R₄ is methyl, R_(h) is NR₆₁, j is 0 to 10, and R_(g)is C(R₄₂R₄₃), wherein NR₆₁ is —R_(hx)—(R_(gx))_(jx)—R_(fx) and R₄₂ andR₄₃ are hydrogen, wherein R_(hx) is C(R_(59x)R_(60x)), jx=0 to 10, andR_(fx) is C(R_(45x)R_(46x)R_(47x)), and wherein R_(59x), R_(60x),R_(45x), R_(46x), R_(47x) are hydrogen. In some embodiments R₄ ismethyl, R_(h) is NR₆₁, j is 0 to 10, R_(g) is C(R₄₂R₄₃), and R_(f) isOH, wherein NR₆₁ is —R_(hx)—(R_(gx))_(jx)—R_(fx) and R₄₂ and R₄₃ arehydrogen, wherein R_(hx) is C(R_(59x)R_(60x)), jx=0 to 10, and R_(fx) isC(R_(45x)R_(46x)R_(47x)), and wherein R_(59x), R_(60x), R_(45x),R_(46x), R_(47x) are hydrogen. In some embodiment j is 0. In someembodiments j is 1. In some embodiment j is 2. In some embodiments j is3. In some embodiment j is 4. In some embodiments j is 5. In someembodiments j is 6. In some embodiments j is 7. In some embodiment j is8. In some embodiments j is 9. In some embodiments j is 10. In someembodiment jx is 0. In some embodiments jx is 1. In some embodiment jxis 2. In some embodiments jx is 3. In some embodiment jx is 4. In someembodiments jx is 5. In some embodiments jx is 6. In some embodiments jxis 7. In some embodiment jx is 8. In some embodiments jx is 9. In someembodiments jx is 10. In some embodiments j=jx. In some embodimentsj=jx+4. In some embodiments j=2*jx. In some embodiments R₄ is hydrogen,methyl, ethyl, or butyl.

In some embodiments R₄ is methyl, R_(h) is NR₆₁, j is 0 to 10, and R_(g)is C(R₄₂R₄₃), wherein NR₆₁ is —R_(hx)—(R_(gx))_(jx)—R_(fx) and R₄₂ andR₄₃ are hydrogen, wherein R_(hx) is C(R_(59x)R_(60x)), jx=0 to 10, andR_(fx) is hydrogen, and wherein R_(59x), R_(60x), R_(45x), R_(46x),R_(47x) are hydrogen. In some embodiments R₄ is methyl, R_(h) is NR₆₁, jis 0 to 10, R_(g) is C(R₄₂R₁₃), and R_(f) is OH, wherein NR₆₁ is—R_(hx)—(R_(gx))_(jx)—R_(fx) and R₄₂ and R₄₃ are hydrogen, whereinR_(hx) is C(R_(59x)R_(60x)), jx=0 to 10, and R_(fx) is hydrogen, andwherein R_(59x), R_(60x), R_(45x), R_(46x), R_(47x) are hydrogen. Insome embodiment j is 0. In some embodiments j is 1. In some embodiment jis 2. In some embodiments j is 3. In some embodiment j is 4. In someembodiments j is 5. In some embodiments j is 6. In some embodiments j is7. In some embodiment j is 8. In some embodiments j is 9. In someembodiments j is 10. In some embodiment jx is 0. In some embodiments jxis 1. In some embodiment jx is 2. In some embodiments jx is 3. In someembodiment jx is 4. In some embodiments jx is 5. In some embodiments jxis 6. In some embodiments jx is 7. In some embodiment jx is 8. In someembodiments jx is 9. In some embodiments jx is 10. In some embodimentsj=jx. In some embodiments j=jx+4. In some embodiments j=2*jx. In someembodiments R₄ is hydrogen, methyl, ethyl, or butyl.

O1

In some embodiments, in Formula IX, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ arecarbon, y is 0, the ring of Formula IX is aromatic, R₂₄ is—(CR₂₅R₂₅)_(p)—, both R₂₅ are hydrogen, and p is 1.

O3

In some embodiments, in Formula XIV, R₁₉ is oxygen, R₁₈, R₂₀, R₂₁, andR₂₂ are carbon, w is 0, the ring of Formula XIV has no double bonds, R₂₄is —(CR₂₅R₂₅)_(p)—, both R₂₅ are hydrogen, and p is 1.

O4

In some embodiments, R_(h) is C(R₅₉R₆₀), j is 0, R_(f) is C(R₄₅R₄₆R₄₇),wherein R₄₅, R₄₆, and R₄₇ are fluorine, wherein R₅₉ and R₆₀ arehydrogen. In some embodiments, j is an integer from 0 to 5, wherein eachR_(g) is C(R₄₂R₄₃), wherein R₄₂ and R₄₃ are hydrogen. In someembodiments, j is 1. In some embodiments, j is 2. In some embodiments, jis 3. In some embodiments, j is 4. In some embodiments, j is 5.

O5

In some embodiments R_(h) is C(R₅₉R₆₀), j is 2, and R_(g) is C(R₄₂R₄₃),wherein R₄₂ and R₄₃ are absent and R₅₉ and R₆₀ are hydrogen. In someembodiments R_(h) is C(R₅₉R₆₀), j is 2, R_(g) is C(R₄₂R₄₃), and R_(f) ishydrogen, wherein R₄₂ and R₄₃ are absent and R₅₉ and R₆₀ are hydrogen.In some embodiments R_(h) is C(R₅₉R₆₀), j is 2 to 12, and R_(g) isC(R₄₂R₄₃), wherein R₄₂ and R₄₃ are absent on one pair of adjacent R_(g),R₄₂ and R₄₃ are hydrogen on the other R_(g), and R₅₉ and R₆₀ arehydrogen. In some embodiments R_(h) is C(R₅₉R₆₀), j is 2 to 12, R_(g) isC(R₄₂R₄₃), and R_(f) is hydrogen, wherein R₄₂ and R₄₃ are absent on onepair of adjacent R_(g), R₄₂ and R₄₃ are hydrogen on the other R_(g), andR₅₉ and R₆₀ are hydrogen. In some embodiments R₄₂ and R₄₃ are absent onthe first and second R_(g). In some embodiments R₄₂ and R₄₃ are absenton the second and third R_(g). In some embodiments R₄₂ and R₄₃ areabsent on the third and fourth R_(g). In some embodiments R₄₂ and R₄₃are absent on the fourth and fifth R_(g). In some embodiments R₄₂ andR₄₃ are absent on the fifth and sixth R_(g). In some embodiments R₄₂ andR₄₃ are absent on the sixth and seventh R_(g). In some embodiments R₄₂and R₄₃ are absent on the seventh and eighth R_(g). In some embodimentsR₄₂ and R₄₃ are absent on the eighth and ninth R_(g). In someembodiments R₄₂ and R₄₃ are absent on the ninth and tenth R_(g). In someembodiments R₄₂ and R₄₃ are absent on the tenth and eleventh R_(g). Insome embodiments R₄₂ and R₄₃ are absent on the eleventh and twelfthR_(g).

O6

In some embodiments, in Formula XIV, R₁₉ is oxygen, R₁₈, R₂₀, R₂₁, andR₂₂ are carbon, w is 0, the ring of Formula XIV has double bonds betweenR₂₀ and R₂₁ and between R₂₂ and R₁₈, R₂₄ is —(CR₂₅R₂₅)_(p)—, both R₂₅are hydrogen, and p is 1.

O7

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, R₂₁ and R₂₂ are absent, R₁₈, R₁₉, and R₂₀ are carbon, w is 3,the ring of Formula XIV has no double bonds, R₂₄ is —(CR₂₅R₂₅)_(p)—, andp is 1, two R^(e) are —CH₃ and one R^(e) is —R_(h)—(R_(g))_(j)—R_(f),R_(h) is C(R₅₉R₆₀), R₅₉ is hydrogen, R₆₀ is absent, j is 0, R_(f) isC(R₄₅R₄₆R₄₇), R₄₅ and R₄₆ are —CH₃, R₄₇ is absent, and there is a doublebond between R_(h) and R_(f), the two R^(e) that are —CH₃ are both onR₁₉ or R₂₀.

In some embodiments, one R^(e) is —CH₃ and two R^(e) are—R_(h)—(R_(g))_(j)—R_(f). In some embodiments, one R^(e) is—R_(h)—(R_(g))_(j)—R_(f), and two R^(e) are —CH₃. In some embodiments,each R^(e) is —R_(h)—(R_(g))_(j)—R_(f). In some embodiments, each R^(e)is —CH₃. In some embodiments, w is 4. In some embodiments, w is 3. Insome embodiments, w is 2. In some embodiments, w is 1. In someembodiments, w is 0.

O8

In some embodiments R_(h) is C(R₅₉R₆₀), and j is 0, wherein R₅₉ and Reoare hydrogen. In some embodiments R_(h) is C(R₅₉R₆₀), and j is 0 to 10,wherein R₅₉ and Reo are hydrogen. In some embodiments R_(h) isC(R₅₉R₆₀), j is 0, and R_(f) is C(R₄₅R₄₆R₄₇), wherein R₅₉, R₆₀, R₄₅,R₄₆, and R₄₇ are hydrogen. In some embodiments R_(h) is C(R₅₉R₆₀), j is0 to 10, and R_(f) is C(R₄₅R₄₆R₄₇), wherein R₅₉, R₆₀, R₄₅, R₄₆, and R₄₇are hydrogen. In some embodiment) is 0. In some embodiments) is 1. Insome embodiment) is 2. In some embodiments) is 3. In some embodiment) is4. In some embodiments) is 5. In some embodiments) is 6. In someembodiments) is 7. In some embodiment) is 8. In some embodiments) is 9.In some embodiments) is 10.

O9

In some embodiments R_(h) is C(R₅₉R₆₀), j is 2, and R_(g) is C(R₄₂R₄₃),wherein R₄₂ and R₄₃ are absent and R₅₀ and R₆₀ are hydrogen. In someembodiments R_(h) is C(R₅₉R₆₀), j is 2 to 12, and R_(g) is C(R₄₂R₄₃),wherein R₄₂ and R₄₃ are absent on one pair of adjacent R_(g), R₄₂ andR₄₃ are hydrogen on the other R_(g), and R₅₉ and R₆₀ are hydrogen. Insome embodiments, R₁₀₀, R₁₀₁, and R₁₀₂ are each independently C₁-C₆alkyl, phenyl, aryl, or C₅-C₆ cyclic. In some embodiments R_(h) isC(R₅₉R₆₀), j is 2, R_(g) is C(R₄₂R₄₃), and R_(f) is Si(R₁₀₀R₁₀₁R₁₀₂),wherein R₁₀₀, R₁₀₁, and R₁₀₂ are methyl, R₄₂ and R₄₃ are absent and R₅₉and Reo are hydrogen. In some embodiments R_(h) is C(R₅₉R₆₀), j is 2 to12, R_(g) is C(R₄₂R₄₃), and R_(f) is Si(R₁₀₀R₁₀₁R₁₀₂), wherein R₁₀₀,R₁₀₁, and R₁₀₂ are each independently alkyl, phenyl, aryl, or C₃-C₂₀cyclic, R₄₂ and R₄₃ are absent on one pair of adjacent R_(g), R₄₂ andR₄₃ are hydrogen on the other R_(g), and R₅₉ and Reo are hydrogen.

In some embodiments, R₁₀₀, R₁₀₁, and R₁₀₂ are each independently C₁-C₃alkyl. In some embodiments R₄₂ and R₄₃ are absent on the first andsecond R_(g). In some embodiments, R₁₀₀, R₁₀₁, and R₁₀₂ are eachindependently C₁-C₆ alkyl, phenyl, aryl, or C₅-C₆ cyclic. In someembodiments, R₁₀₀, R₁₀₁, and R₁₀₂ are each independently C₁-C₃ alkyl.

In some embodiments R₄₂ and R₄₃ are absent on the first and secondR_(g). In some embodiments R₄₂ and R₄₃ are absent on the second andthird R_(g). In some embodiments R₄₂ and R₄₃ are absent on the third andfourth R_(g). In some embodiments R₄₂ and R₄₃ are absent on the fourthand fifth R_(g). In some embodiments R₄₂ and R₄₃ are absent on the fifthand sixth R_(g). In some embodiments R₄₂ and R₄₃ are absent on the sixthand seventh R_(g). In some embodiments R₄₂ and R₄₃ are absent on theseventh and eighth R_(g). In some embodiments R₄₂ and R₄₃ are absent onthe eighth and ninth R_(g). In some embodiments R₄₂ and R₄₃ are absenton the ninth and tenth R_(g). In some embodiments R₄₂ and R₄₃ are absenton the tenth and eleventh R_(g). In some embodiments R₄₂ and R₄₃ areabsent on the eleventh and twelfth R_(g).

O10

In some embodiments R_(h) is C(R₅₉R₆₀), and j is 0, wherein R₅₉ and R₆₀are hydrogen. In some embodiments R_(h) is C(R₅₉R₆₀), and j is 0,wherein R₅₉ and R₆₀ are —C(R₅₆R₅₇R₅₈), and R₅₆, R₅₇, and R₅₈ arehydrogen. In some embodiments R_(h) is C(R₅₉R₆₀), j is 0, and R_(f) ishydrogen, wherein R₅₉ and R₆₀ are hydrogen. In some embodiments R_(h) isC(R₅₉R₆₀), j is 0, and R_(f) is C(R₄₅R₄₆R₄₇), wherein R₅₉, R₆₀, R₄₅,R₄₆, and R₄₃ are hydrogen. In some embodiments R_(h) is C(R₅₉R₆₀), j is0, and R_(f) is C(R₄₅R₄₆R₄₇), wherein R₅₉ and Reo are —C(R₅₆R₅₇R₅₈), andR₄₅, R₄₆, Rn, R₅₆, R₅₇, and R₅₈ are hydrogen.

O11

In some embodiments, in Formula IX, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ arecarbon, y is 1, R^(e) is —OH, the ring of Formula IX is aromatic, R₂₄ is—(CR₂₅R₂₅)_(p)—, both R₂₅ are hydrogen, and p is 1. In some embodiments,R^(e) is at position R₂₁.

O12 In some embodiments, in Formula IX, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃are carbon, y is 1, R^(e) is —O—CH₃, the ring of Formula IX is aromatic,R₂₄ is —(CR₂₅R₂₅)_(p)—, both R₂₅ are hydrogen, and p is 1. In someembodiments, R^(e) is at position R₂₁.

Y1

In some embodiments, in Formula IX, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ arecarbon, y is 1, R^(e) is hydroxy, the ring of Formula IX has no doublebonds, R₂₄ is —(CR₂₅R₂₅)_(p)—, and p is 0. In some embodiments, R^(e) isat R₂₁. In some embodiments, R^(e) is at R₁₉. In some embodiments, R^(e)is at R₂₀. In some embodiments, R^(e) is at R₂₂. In some embodiments,R^(e) is at R₂₃.

Y2

In some embodiments, in Formula IX, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ arecarbon, y is 1, R^(e) is —O—CH₃, the ring of Formula IX is aromatic, R₂₄is —(CR₂₅R₂₅)_(p)—, and p is 0. In some embodiments, R^(e) is at R₂₁. Insome embodiments, R^(e) is at R₁₉. In some embodiments, R^(e) is at R₂₀.In some embodiments, R^(e) is at R₂₂. In some embodiments, R^(e) is atR₂₃.

Y3

Independently in some embodiments of Formula XIV, and independently incombination with any embodiments of any other relevant substituentclasses, R₁₉ and R₂₁ are nitrogen, R₁₈, R₂₀, and R₂₂ are carbon, w is 1,the ring of Formula XIV has double bonds between R₂₀ and R₂₁ and betweenR₂₂ and R₁₈, R₂₄ is —(CR₂₅R₂₅)_(p)—, and p is 0.

Y4

In some embodiments, in Formula IX, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ arecarbon, y is 1, R^(e) is —CH₂—OH, the ring of Formula IX is aromatic,R₂₄ is —(CR₂₅R₂₅)_(p)—, and p is 0. In some embodiments, R^(e) is atR₂₁. In some embodiments, R^(e) is at R₁₉. In some embodiments, R^(e) isat R₂₀. In some embodiments, R^(e) is at R₂₂. In some embodiments, R^(e)is at R₂₃.

Y5

In some embodiments, in Formula IX, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ arecarbon, y is 1, R^(e) is methyl, the ring of Formula IX is aromatic, R₂₄is —(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, p is 0, q is 0, and X_(b) isS(O)₂.

Y6 Left

In some embodiments R_(h) is NR₆₁, j is 1, and R_(g) is C(R₄₂R₄₃),wherein R₆₁ is —R_(hx)—(R_(gx))_(jx)—R_(fx), and R₄₂ and R₄₃ arehydrogen, wherein R_(hx) is absent, jx=1, R_(gx) is C(R_(42x)R_(43x)),and R_(fx) is C(R_(45x)R_(46x)R_(47x)), and wherein R_(42x), R_(43x),R_(45x), R_(46x), R_(47x) are hydrogen. In some embodiments R_(h) isNR₆₁, j is 1, R_(g) is C(R₄₂R₄₃), and R_(f) is C(R₄₅R₄₆R₄₇), wherein R₆₁is —R_(hx)—(R_(gx))_(jx)—R_(fx), and R₄₂, R₄₃, R₄₅, R₄₆, and R₄₇ arehydrogen, wherein R_(hx) is absent, jx=1, R_(gx) is C(R_(42x)R_(43x)),and R_(fx) is C(R_(45x)R_(46x)R_(47x)), and wherein R_(42x), R_(43x),R_(45x), R_(46x), R_(47x) are hydrogen.

In some embodiments R_(h) is NR₆₁, j is 0 to 10, and each R_(g) isC(R₄₂R₄₃), wherein Ru is —R_(hx)—(R_(gx))_(jx)—R_(fx), and R₄₂ and R₄₃are hydrogen, wherein R_(hx) is C(R_(59x)R_(60x)), jx=0 to 10, R_(gx) isC(R_(42x)R_(43x)), and R_(fx) is C(R_(45x)R_(46x)R_(47x)), and whereinR_(59x), R_(60x), R_(42x), R_(43x), R_(45x), R_(46x), R_(47x) arehydrogen. In some embodiments R_(h) is NR₆₁, j is 0 to 10, each R_(g) isC(R₄₂R₄₃), and R_(f) is C(R₄₅R₄₆R₄₇), wherein R₆₁ is—R_(hx)—(R_(gx))_(jx)—R_(fx), and R₄₂, R₄₃, R₄₅, R₄₆, and R₄₇ arehydrogen, wherein R_(hx) is C(R_(59x)R_(60x)), jx=0 to 10, R_(gx) isC(R_(42x)R_(43x)), and R_(fx) is C(R_(45x)R_(46x)R_(47x)), and whereinR_(59x), R_(60x), R_(42x), R_(43x), R_(45x), R_(46x), R_(47x) arehydrogen. In some embodiments j=jx. In some embodiments j and jx are 0.In some embodiment j and jx are 2. In some embodiments j and jx are 3.In some embodiments j and jx are 4.

Y6 Right

In some embodiments R_(h) is C(R₅₉R₆₀), and j is 0, wherein R₅₉ and R₆₀are hydrogen. In some embodiments R_(h) is C(R₅₉R₆₀), j is 0 to 10, andeach R_(g) is C(R₄₂R₄₃), wherein R₅₉, R₆₀R₄₂, R₄₃ are hydrogen. In someembodiments R_(h) is C(R₅₉R₆₀), j is 0, and R_(f) is OH, wherein R₅₉ andR₆₀ are hydrogen. In some embodiments R_(h) is C(R₅₉R₆₀), j is 0 to 10,each R_(g) is C(R₄₂R₄₃), and R_(f) is OH, wherein R₅₉, R₆₀R₄₂, R₄₃ arehydrogen. In some embodiments j is 1. In some embodiment j is 2. In someembodiments j is 3. In some embodiments j is 4.

Y7

In some embodiments R_(h) is C(R₅₉R₆₀), j is 1, and R_(g) is O, whereinR₅₉, R₆₀, R₄₅, R₄₆, and R₄₇ are hydrogen. In some embodiments R_(h) isabsent, j is 1, and R_(g) is O. In some embodiments R_(h) is C(R₅₉R₆₀),j is 1, R_(g) is O, and R_(f) is C(R₄₅R₄₆R₄₇), wherein R₅₉, R₆₀, R₄₅,R₄₆, and R₄₇ are hydrogen. In some embodiments R_(h) is absent, j is 1,R_(g) is O, and R_(f) is C(R₄₅R₄₆R₄₇), wherein R₄₅, R₄₆, and R₄₇ arehydrogen.

In some embodiments R_(h) is C(R₅₉R₆₀), j is 1 to 10, one R_(g) is O,and the other R_(g) are C(R₄₂R₄₃), wherein R₅₉, R₆₀, R₄₂, and R₄₃ arehydrogen. In some embodiments the last R_(g) is O. In some embodimentsthe penultimate R_(g) is O. In some embodiments the antepenultimateR_(g) is O. In some embodiments the fourth from the last R_(g) is O. Insome embodiments the fifth from the last R_(g) is O. In some embodimentsthe first R_(g) is O. In some embodiments the second R_(g) is O. In someembodiments the third R_(g) is O. In some embodiments the fourth R_(g)is O. In some embodiments the fifth R_(g) is O.

In some embodiments R_(h) is C(R₅₉R₆₀), j is 1 to 10, one R_(g) is O,the other R_(g) are C(R₄₂R₄₃), and R_(f) is C(R₄₅R₄₆R₄₇), wherein R₅₉,R₆₀, R₄₂, R₄₃, R₄₅, R₄₆, and R₄₃ are hydrogen. In some embodiments thelast R_(g) is O. In some embodiments the penultimate R_(g) is O. In someembodiments the antepenultimate R_(g) is O. In some embodiments thefourth from the last R_(g) is O. In some embodiments the fifth from thelast R_(g) is O. In some embodiments the first R_(g) is O. In someembodiments the second R_(g) is O. In some embodiments the third R_(g)is O. In some embodiments the fourth R_(g) is O. In some embodiments thefifth R_(g) is O.

Y9 Left

In some embodiments, R₈ is —COOH and in Formula IX, R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are carbon, y is 0, the ring of Formula IX is aromatic, R₂₄is —(CR₂₅R₂₅)_(p)—, and p is 0.

Y9 Right

In some embodiments R_(h) is C(R₅₉R₆₀), and j is 0, wherein R₅₉ is ═Oand R₆₀ is —OH. In some embodiments R_(h) is absent, j is 0 to 10, andeach R_(g) is C(R₄₂R₄₃), wherein R₄₂ and R₄₃ are hydrogen. In someembodiments R_(h) is absent, j is 0, and R_(f) is C(R₄₅R₄₆R₄₇), whereinR₄₅ is ═O, R₄₃ is —OH, and R₄₇ is absent. In some embodiments R_(h) isabsent, j is 0 to 10, each R_(g) is C(R₄₂R₄₃), and R_(f) isC(R₄₅R₄₆R₄₇), wherein R₄₃ is ═O, R₄₆ is —OH, R₄₇ is absent, and R₄₂ andR₄₃ are hydrogen.

Y10

In some embodiments R_(h) is absent, j is 6, and each R_(g) isC(R₄₂R₄₃), wherein R₄₂ and R₄₃ are hydrogen. In some embodiments R_(h)is absent, j is 1 to 10, and each R_(g) is C(R₄₂R₄₃), wherein R₄₂ andR₄₃ are hydrogen. In some embodiments R_(h) is absent, j is 6, eachR_(g) is C(R₄₂R₄₃), and R_(f) is C(R₄₅R₄₆R₄₇), wherein R₄₂, R₄₃, R₄₅,R₄₆, and R₄₃ are hydrogen. In some embodiments R_(h) is absent, j is 1to 10, each R_(g) is C(R₄₂R₄₃), and R_(f) is C(R₄₅R₄₆R₄₇), wherein R₄₂,R₄₃, R₄₅, R₄₆, and R₄₇ are hydrogen. In some embodiments j is 3. In someembodiment j is 4. In some embodiments j is 5. In some embodiments j is7. In some embodiment j is 8. In some embodiments j is 9. In someembodiments j is 10.

Y11

In some embodiments R_(h) is C(R₅₉R₆₀), j is 3, the first R_(g) is O,and the second and third R_(g) are C(R₄₂R₄₃), wherein R₅₉, R₆₀, R₄₂, andR₄₃ are hydrogen. In some embodiments R_(h) is C(R₅₉R₆₀), j is 1 to 10,one R_(g) is O, and the other R_(g) are C(R₄₂R₄₃), wherein R₅₉, R₆₀,R₄₂, and R₄₃ are hydrogen. In some embodiments R_(h) is C(R₅₉R₆₀), j is3, the first R_(g) is O, the second and third R_(g) are C(R₄₂R₄₃), andR_(f) is OH, wherein R₅₉, R₆₀, R₄₂, and R₄₃ are hydrogen. In someembodiments R_(h) is C(R₅₉R₆₀), j is 1 to 10, one R_(g) is O, the otherR_(g) are C(R₄₂R₄₃), and R_(f) is OH, wherein R₅₉, R₆₀, R₄₂, and R₄₃ arehydrogen. In some embodiments the first R_(g) is O. In some embodimentsthe second R_(g) is O. In some embodiments the third R_(g) is O. In someembodiments the fourth R_(g) is O. In some embodiments the fifth R_(g)is O. In some embodiments the fifth from the last R_(g) is O. In someembodiments the fourth from the last R_(g) is O. In some embodiments theantepenultimate R_(g) is O. In some embodiments the penultimate R_(g) isO. In some embodiments the last R_(g) is O.

In some embodiments R_(h) is C(R₅₉R₆₀), j is 4 to 16, two R_(g) are O,and the other R_(g) are C(R₄₂R₄₃), wherein R₅₉, R₆₀, R₄₂, and R₄₃ arehydrogen. In some embodiments R_(h) is C(R₅₉R₆₀), j is 4 to 16, twoR_(g) are O, the other R_(g) are C(R₄₂R₄₃), and R_(f) is OH, whereinR₅₉, R₆₀, R₄₂, and R₄₃ are hydrogen.

In some embodiments the first and third R_(g) are O. In some embodimentsthe first and fourth R_(g) are O. In some embodiments the first andfifth R_(g) are O. In some embodiments the first and sixth R_(g) are O.In some embodiments the first and seventh R_(g) are O. In someembodiments the first and eighth R_(g) are O. In some embodiments thefirst and ninth R_(g) are O. In some embodiments the first and tenthR_(g) are O. In some embodiments the first and eleventh R_(g) are O. Insome embodiments the first and twelfth R_(g) are O. In some embodimentsthe first and thirteenth R_(g) are O. In some embodiments the first andfourteenth R_(g) are O. In some embodiments the first and fifteenthR_(g) are O. In some embodiments the second and fourth R_(g) are O. Insome embodiments the second and fifth R_(g) are O. In some embodimentsthe second and sixth R_(g) are O. In some embodiments the second andseventh R_(g) are O. In some embodiments the second and eighth R_(g) areO. In some embodiments the second and ninth R_(g) are O. In someembodiments the second and tenth R_(g) are O. In some embodiments thesecond and eleventh R_(g) are O. In some embodiments the second andtwelfth R_(g) are O. In some embodiments the second and thirteenth R_(g)are O. In some embodiments the second and fourteenth R_(g) are O. Insome embodiments the second and fifteenth R_(g) are O. In someembodiments the third and fifth R_(g) are O. In some embodiments thethird and sixth R_(g) are O. In some embodiments the third and seventhR_(g) are O. In some embodiments the third and eighth R_(g) are O. Insome embodiments the third and ninth R_(g) are O. In some embodimentsthe third and tenth R_(g) are O. In some embodiments the third andeleventh R_(g) are O. In some embodiments the third and twelfth R_(g)are O. In some embodiments the third and thirteenth R_(g) are O. In someembodiments the third and fourteenth R_(g) are O. In some embodimentsthe third and fifteenth R_(g) are O. In some embodiments the fourth andsixth R_(g) are O. In some embodiments the fourth and seventh R_(g) areO. In some embodiments the fourth and eighth R_(g) are O. In someembodiments the fourth and ninth R_(g) are O. In some embodiments thefourth and tenth R_(g) are O. In some embodiments the fourth andeleventh R_(g) are O. In some embodiments the fourth and twelfth R_(g)are O. In some embodiments the fourth and thirteenth R_(g) are O. Insome embodiments the fourth and fourteenth R_(g) are O. In someembodiments the fourth and fifteenth R_(g) are O. In some embodimentsthe fifth and seventh R_(g) are O. In some embodiments the fifth andeighth R_(g) are O. In some embodiments the fifth and ninth R_(g) are O.In some embodiments the fifth and tenth R_(g) are O. In some embodimentsthe fifth and eleventh R_(g) are O. In some embodiments the fifth andtwelfth R_(g) are O. In some embodiments the fifth and thirteenth R_(g)are O. In some embodiments the fifth and fourteenth R_(g) are O. In someembodiments the fifth and fifteenth R_(g) are O. In some embodiments thesixth and eighth R_(g) are O. In some embodiments the sixth and ninthR_(g) are O. In some embodiments the sixth and tenth R_(g) are O. Insome embodiments the sixth and eleventh R_(g) are O. In some embodimentsthe sixth and twelfth R_(g) are O. In some embodiments the sixth andthirteenth R_(g) are O. In some embodiments the sixth and fourteenthR_(g) are O. In some embodiments the sixth and fifteenth R_(g) are O. Insome embodiments the seventh and ninth R_(g) are O. In some embodimentsthe seventh and tenth R_(g) are O. In some embodiments the seventh andeleventh R_(g) are O. In some embodiments the seventh and twelfth R_(g)are O. In some embodiments the seventh and thirteenth R_(g) are O. Insome embodiments the seventh and fourteenth R_(g) are O. In someembodiments the seventh and fifteenth R_(g) are O. In some embodimentsthe eighth and tenth R_(g) are O. In some embodiments the eighth andeleventh R_(g) are O. In some embodiments the eighth and twelfth R_(g)are O. In some embodiments the eighth and thirteenth R_(g) are O. Insome embodiments the eighth and fourteenth R_(g) are O. In someembodiments the eighth and fifteenth R_(g) are O. In some embodimentsthe ninth and eleventh R_(g) are O. In some embodiments the ninth andtwelfth R_(g) are O. In some embodiments the ninth and thirteenth R_(g)are O. In some embodiments the ninth and fourteenth R_(g) are O. In someembodiments the ninth and fifteenth R_(g) are O. In some embodiments thetenth and twelfth R_(g) are O. In some embodiments the tenth andthirteenth R_(g) are O. In some embodiments the tenth and fourteenthR_(g) are O. In some embodiments the tenth and fifteenth R_(g) are O. Insome embodiments the eleventh and thirteenth R_(g) are O. In someembodiments the eleventh and fourteenth R_(g) are O. In some embodimentsthe eleventh and fifteenth R_(g) are O. In some embodiments the twelfthand fourteenth R_(g) are O. In some embodiments the twelfth andfifteenth R_(g) are O. In some embodiments the thirteenth and fifteenthR_(g) are O.

Y12

In some embodiments, in Formula IX, R₁₉ is O, R₁₈, R₂₀, R₂₁, R₂₂, andR₂₃ are carbon, y is 0, the ring of Formula IX has no double bonds, R₂₄is —(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, p is 0, q is 1, both R₂₅ arehydrogen, and X_(b) is O.

Y13

In some embodiments, in Formula IX, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ arecarbon, y is 0, the ring of Formula IX is aromatic, R₂₄ is—(CR₂₅R₂₅)_(p)—, one R₂₅ is —OH, the other R₂₅ is hydrogen, and p is 1.

Y14

In some embodiments, in Formula IX, R₂₀ is N, R₁₈, R₁₉, R₂₁, R₂₂, andR₂₃ are carbon, y is 0, the ring of Formula IX is aromatic, R₂₄ is—(CR₂₅R₂₅)_(p)—, and p is 0).

Y15

In some embodiments, in Formula IX, R₁₈ is N, R₂₁ is S(O)₂, R₁₉, R₂₀,R₂₂, and R₂₃ are carbon, the ring of Formula IX has no double bonds, R₂₄is —(CR₂₅R₂₅)_(p)—, p is 1, both R₂₅ are hydrogen.

Y16

In some embodiments R_(h) is C(R₅₉R₆₀), and j is 0, wherein R₅₉ and R₆₀are hydrogen. In some embodiments R_(h) is C(R₅₉R₆₀), j is 0 to 10, andeach R_(g) is C(R₄₂R₄₃), wherein R₅₉, R₆₀, R₄₂, and R₄₃ are hydrogen. Insome embodiments R_(h) is C(R₅₉R₆₀), j is 0, and R_(f) is hydrogen,wherein R₅₉ and R₆₀ are hydrogen. In some embodiments R_(h) isC(R₅₉R₆₀), j is 0 to 10, each R_(g) is C(R₄₂R₄₃), and R_(f) is hydrogen,wherein R₅₉, R₆₀, R₄₂, and R₄₃ are hydrogen. In some embodiments j is 1.In some embodiment j is 2. In some embodiments j is 3. In someembodiment j is 4. In some embodiments j is 5. In some embodiments j is7. In some embodiment j is 8. In some embodiments j is 9. In someembodiments j is 10.

In some embodiments R_(h) is C(R₅₉R₆₀), j is 0 to 10, and each R_(g) isC(R₄₂R₄₃), wherein R₅₉ is —R_(hx)—(R_(gx))_(jx)—R_(fx), and R₆₀, R₄₂,and R₄₃ are hydrogen, wherein R_(hx) is C(R_(59x)R_(60x)), jx is 0, andR_(fx) is hydrogen, wherein R_(59x) and R_(60x) are hydrogen. In someembodiments j is 0. In some embodiments j is 1. In some embodiment j is2. In some embodiments j is 3. In some embodiment j is 4. In someembodiments j is 5. In some embodiments j is 7. In some embodiment j is8. In some embodiments j is 9. In some embodiments j is 10.

In some embodiments R_(h) is C(R₅₉R₆₀), j is 0 to 10, and each R_(g) isC(R₄₂R₄₃), wherein R₅₉ is —R_(hx)—(R_(gx))_(jx)—R_(fx), and R₆₀, R₄₂,and R₄₃ are hydrogen, wherein R_(hx) is C(R_(59x)R_(60x)), jx is 0, andR_(fx) is hydrogen, wherein R_(59x) and R_(60x) are hydrogen. In someembodiments R_(h) is C(R₅₉R₆₀), j is 0 to 10, each R_(g) is C(R₄₂R₄₃),and R_(f) is hydrogen, wherein R₅₉ is —R_(hx)—(R_(gx))_(jx)—R_(fx), andR₆₀, R₄₂, and R₄₃ are hydrogen, wherein R_(hx) is C(R_(59x)R_(60x)), jxis 0, and R_(fx) is hydrogen, wherein R_(59x) and R_(60x) are hydrogen.In some embodiments j is 1. In some embodiment j is 2. In someembodiments j is 3. In some embodiment j is 4. In some embodiments j is5. In some embodiments j is 7. In some embodiment j is 8. In someembodiments j is 9. In some embodiments j is 10. In some embodiments jxis 1. In some embodiment jx is 2. In some embodiments jx is 3. In someembodiment jx is 4. In some embodiments jx is 5. In some embodiments jxis 7. In some embodiment jx is 8. In some embodiments jx is 9. In someembodiments jx is 10. In some embodiments j=jx.

Y17

In some embodiments, in Formula IX, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ arecarbon, y is 0, the ring of Formula IX is aromatic, R₂₄ is—(CR₂₅R₂₅)_(p)—, and p is 0.

Y18

In some embodiments R_(h) is C(R₅₉R₆₀), and j is 0, wherein R₅₉ is ═O,and R₆₀ is absent. In some embodiments R_(h) is C(R₅₉R₆₀), j is 0, andR_(f) is C(R₄₅R₄₆R₄₇), wherein R₅₉ is ═O, R₆₀ is absent, and R₄₅, R₄₆,and R₄₇ are hydrogen. In some embodiments R_(h) is C(R₅₉R₆₀), j is 0 to10, and each R_(g) is C(R₄₂R₄₃), wherein R₅₉ is ═O, R₆₀ is absent, andR₄₂ and R₄₃ are hydrogen. In some embodiments R_(h) is C(R₅₉R₆₀), j is 0to 10, each R_(g) is C(R₄₂R₄₃), and R_(f) is C(R₄₅R₄₆R₄₇), wherein R₅₉is ═O, R₆₀ is absent, and R₄₂, R₄₃, R₄₅, R₄₆, and R₄₇ are hydrogen. Insome embodiments j is 1. In some embodiment j is 2. In some embodimentsj is 3. In some embodiment j is 4. In some embodiments j is 5. In someembodiments j is 7. In some embodiment j is 8. In some embodiments j is9. In some embodiments j is 10.

In some embodiments R_(h) is C(R₅₉R₆₀), j is 1 to 10, and each R_(g) isC(R₄₂R₄₃), wherein R₄₃ is ═O and R₄₃ is absent for one R_(g), R₄₂ andR₄₃ are hydrogen for the other R_(g), and R₅₉ and R₆₀ are hydrogen. Insome embodiments R_(h) is C(R₅₉R₆₀), j is 1 to 10, each R_(g) isC(R₄₂R₄₃), and R_(f) is C(R₄₅R₄₆R₄₇), wherein R₄₂ is ═O and R₄₃ isabsent for one R_(g), R₄₂ and R₄₃ are hydrogen for the other R_(g), andR₅₉, R₆₀, R₄₅, R₄₆, and R₄₇ are hydrogen. In some embodiments R₄₃ is ═Oand R₄₃ is absent for the last R_(g). In some embodiments R₄₃ is ═O andR₄₃ is absent for the penultimate R_(g). In some embodiments R₄₂ is ═Oand R₄₃ is absent for the antepenultimate R_(g). In some embodiments R₄₂is ═O and R₄₃ is absent for the fourth from the last R_(g). In someembodiments R₄₃ is ═O and R₄₃ is absent for the fifth from the lastR_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent for the firstR_(g). In some embodiments R₄₃ is ═O and R₄₃ is absent for the secondR_(g). In some embodiments R₄₃ is ═O and R₄₃ is absent for the thirdR_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent for the fourthR_(g). In some embodiments R₄₃ is ═O and R₄₃ is absent for the fifthR_(g).

In some embodiments R_(h) is C(R₅₉R₆₀), j is 1 to 15, and each R_(g) isC(R₄₂R₄₃), wherein R₄₂ is ═O and R₄₃ is absent for two R_(g), R₄₂ andR₄₃ are hydrogen for the other R_(g), and R₅₉ and R₆₀ are hydrogen. Insome embodiments R_(h) is C(R₅₉R₆₀), j is 1 to 15, each R_(g) isC(R₄₂R₄₃), and R_(f) is C(R₄₅R₄₆R₄₇), wherein R₄₃ is ═O and R₄₃ isabsent for two R_(g), R₄₂ and R₄₃ are hydrogen for the other R_(g), andR₅₉, R₆₀, R₄₅, R₄₆, and R₄₇ are hydrogen. In some embodiments R₄₃ is ═Oand R₄₃ is absent the first and third R_(g). In some embodiments R₄₃ is═O and R₄₃ is absent the first and fourth R_(g). In some embodiments R₄₃is ═O and R₄₃ is absent the first and fifth R_(g). In some embodimentsR₄₂ is ═O and R₄₃ is absent the first and sixth R_(g). In someembodiments R₄₃ is ═O and R₄₃ is absent the first and seventh R_(g). Insome embodiments R₄₃ is ═O and R₄₃ is absent the first and eighth R_(g).In some embodiments R₄₃ is ═O and R₄₃ is absent the first and ninthR_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent the first andtenth R_(g). In some embodiments R₄₃ is ═O and R₄₃ is absent the firstand eleventh R_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent thefirst and twelfth R_(g). In some embodiments R₄₃ is ═O and R₄₃ is absentthe first and thirteenth R_(g). In some embodiments R₄₂ is ═O and R₄₃ isabsent the first and fourteenth R_(g). In some embodiments R₄₃ is ═O andR₄₃ is absent the first and fifteenth R_(g). In some embodiments R₄₂ is═O and R₄₃ is absent the second and fourth R_(g). In some embodimentsR₄₂ is ═O and R₄₃ is absent the second and fifth R_(g). In someembodiments R₄₂ is ═O and R₄₃ is absent the second and sixth R_(g). Insome embodiments R₄₂ is ═O and R₄₃ is absent the second and seventhR_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent the second andeighth R_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent the secondand ninth R_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent thesecond and tenth R_(g). In some embodiments R₄₂ is ═O and R₄₃ is absentthe second and eleventh R_(g). In some embodiments R₄₂ is ═O and R₄₃ isabsent the second and twelfth R_(g). In some embodiments R₄₂ is ═O andR₄₃ is absent the second and thirteenth R_(g). In some embodiments R₄₂is ═O and R₄₃ is absent the second and fourteenth R_(g). In someembodiments R₄₂ is ═O and R₄₃ is absent the second and fifteenth R_(g).In some embodiments R₄₂ is ═O and R₄₃ is absent the third and fifthR_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent the third andsixth R_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent the thirdand seventh R_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent thethird and eighth R_(g). In some embodiments R₄₂ is ═O and R₄₃ is absentthe third and ninth R_(g). In some embodiments R₄₂ is ═O and R₄₃ isabsent the third and tenth R_(g). In some embodiments R₄₂ is ═O and R₄₃is absent the third and eleventh R_(g). In some embodiments R₄₂ is ═Oand R₄₃ is absent the third and twelfth R_(g). In some embodiments R₄₂is ═O and R₄₃ is absent the third and thirteenth R_(g). In someembodiments R₄₂ is ═O and R₄₃ is absent the third and fourteenth R_(g).In some embodiments R₄₂ is ═O and R₄₃ is absent the third and fifteenthR_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent the fourth andsixth R_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent the fourthand seventh R_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent thefourth and eighth R_(g). In some embodiments R₄₂ is ═O and R₄₃ is absentthe fourth and ninth R_(g). In some embodiments R₄₂ is ═O and R₄₃ isabsent the fourth and tenth R_(g). In some embodiments R₄₂ is ═O and R₄₃is absent the fourth and eleventh R_(g). In some embodiments R₄₂ is ═Oand R₄₃ is absent the fourth and twelfth R_(g). In some embodiments R₄₂is ═O and R₄₃ is absent the fourth and thirteenth R_(g). In someembodiments R₄₂ is ═O and R₄₃ is absent the fourth and fourteenth R_(g).In some embodiments R₄₂ is ═O and R₄₃ is absent the fourth and fifteenthR_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent the fifth andseventh R_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent the fifthand eighth R_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent thefifth and ninth R_(g). In some embodiments R₄₂ is ═O and R₄₃ is absentthe fifth and tenth R_(g). In some embodiments R₄₂ is ═O and R₄₃ isabsent the fifth and eleventh R_(g). In some embodiments R₄₂ is ═O andR₄₃ is absent the fifth and twelfth R_(g). In some embodiments R₄₂ is ═Oand R₄₃ is absent the fifth and thirteenth R_(g). In some embodimentsR₄₂ is ═O and R₄₃ is absent the fifth and fourteenth R_(g). In someembodiments R₄₂ is ═O and R₄₃ is absent the fifth and fifteenth R_(g).In some embodiments R₄₂ is ═O and R₄₃ is absent the sixth and eighthR_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent the sixth andninth R_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent the sixthand tenth R_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent thesixth and eleventh R_(g). In some embodiments R₄₂ is ═O and R₄₃ isabsent the sixth and twelfth R_(g). In some embodiments R₄₂ is ═O andR₄₃ is absent the sixth and thirteenth R_(g). In some embodiments R₄₂ is═O and R₄₃ is absent the sixth and fourteenth R_(g). In some embodimentsR₄₂ is ═O and R₄₃ is absent the sixth and fifteenth R_(g). In someembodiments R₄₂ is ═O and R₄₃ is absent the seventh and ninth R_(g). Insome embodiments R₄₂ is ═O and R₄₃ is absent the seventh and tenthR_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent the seventh andeleventh R_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent theseventh and twelfth R_(g). In some embodiments R₄₂ is ═O and R₄₃ isabsent the seventh and thirteenth R_(g). In some embodiments R₄₂ is ═Oand R₄₃ is absent the seventh and fourteenth R_(g). In some embodimentsR₄₂ is ═O and R₄₃ is absent the seventh and fifteenth R_(g). In someembodiments R₄₂ is ═O and R₄₃ is absent the eighth and tenth R_(g). Insome embodiments R₄₂ is ═O and R₄₃ is absent the eighth and eleventhR_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent the eighth andtwelfth R_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent theeighth and thirteenth R_(g). In some embodiments R₄₂ is ═O and R₄₃ isabsent the eighth and fourteenth R_(g). In some embodiments R₄₂ is ═Oand R₄₃ is absent the eighth and fifteenth R_(g). In some embodimentsR₄₂ is ═O and R₄₃ is absent the ninth and eleventh R_(g). In someembodiments R₄₂ is ═O and R₄₃ is absent the ninth and twelfth R_(g). Insome embodiments R₄₂ is ═O and R₄₃ is absent the ninth and thirteenthR_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent the ninth andfourteenth R_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent theninth and fifteenth R_(g). In some embodiments R₄₂ is ═O and R₄₃ isabsent the tenth and twelfth R_(g). In some embodiments R₄₂ is ═O andR₄₃ is absent the tenth and thirteenth R_(g). In some embodiments R₄₂ is═O and R₄₃ is absent the tenth and fourteenth R_(g). In some embodimentsR₄₂ is ═O and R₄₃ is absent the tenth and fifteenth R_(g). In someembodiments R₄₂ is ═O and R₄₃ is absent the eleventh and thirteenthR_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent the eleventh andfourteenth R_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent theeleventh and fifteenth R_(g). In some embodiments R₄₂ is ═O and R₄₃ isabsent the twelfth and fourteenth R_(g). In some embodiments R₄₂ is ═Oand R₄₃ is absent the twelfth and fifteenth R_(g). In some embodimentsthe thirteenth and fifteenth R_(g).

Y19

In some embodiments, in Formula IX, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ arecarbon, y is 1, R^(e) is —NH₂, the ring of Formula IX is aromatic, R₂₄is —(CR₂₅R₂₅)_(p)—, and p is 0. In some embodiments, R^(e) is at R₂₁. Insome embodiments, R^(e) is at R₁₉. In some embodiments, R^(e) is at R₂₀.In some embodiments, R^(e) is at R₂₂. In some embodiments, R^(e) is atR₂₃.

Y20

In some embodiments R_(h) is C(R₅₉R₆₀), j is 6, each R_(g) is C(R₄₂R₄₃),and R_(f) is C(R₄₅R₄₆R₄₇), wherein R₅₉, R₆₀, R₄₅, R₄₆, and R₄₇ arehydrogen, wherein R₄₃ of the first R_(g) is C(R₅₆R₅₇R₅₈), R₄₃ of thefirst through sixth R_(g) are hydrogen, and R₄₂ of the second throughsixth R_(g) are hydrogen, wherein R₅₆ is ═O, R₅₇ is —OH, and R₅₈ isabsent. In some embodiments R_(h) is C(R₅₉R₆₀), j is 6, and each R_(g)is C(R₄₂R₄₃), wherein R₅₉ and Reo are hydrogen, wherein R₄₃ of the firstR_(g) is C(R₅₆R₅₇R₅₈), R₄₃ of the first through sixth R_(g) arehydrogen, and R₄₂ of the second through sixth R_(g) are hydrogen,wherein R₅₆ is ═O, R₅₇ is —OH, and R₅₈ is absent.

In some embodiments R_(h) is C(R₅₉R₆₀), j is 1 to 10, each R_(g) isC(R₄₂R₄₃), and R_(f) is C(R₄₅R₄₆R₄₇), wherein R₅₉, R₆₀, R₄₅, R₄₆, andR₄₇ are hydrogen, wherein R₄₃ of one R_(g) is C(R₅₆R₅₇R₅₈), R₄₂ of theother R_(g) are hydrogen, and R₄₃ is hydrogen, and, wherein R₅₆ is ═O,R₅₇ is —OH, and R₅₈ is absent. In some embodiments R₄₂ of the firstR_(g) is C(R₅₆R₅₇R₅₈). In some embodiments R_(h) is C(R₅₉R₆₀), j is 1 to10, and each R_(g) is C(R₄₂R₄₃), wherein R₅₉ and Reo are hydrogen,wherein R₄₃ of one R_(g) is C(R₅₆R₅₇R₅₈), R₄₂ of the other R_(g) arehydrogen, and R₄₃ is hydrogen, and, wherein R₅₆ is ═O, R₅₇ is —OH, andR₅₈ is absent. In some embodiments R₄₃ of the first R_(g) isC(R₅₆R₅₇R₅₈). In some embodiments R₄₂ of the second R_(g) isC(R₅₆R₅₇R₅₈). In some embodiments R₄₂ of the third R_(g) isC(R₅₆R₅₇R₅₈). In some embodiments R₄₂ of the fourth R_(g) isC(R₅₆R₅₇R₅₈). In some embodiments R₄₂ of the fifth R_(g) isC(R₅₆R₅₇R₅₈). In some embodiments R₄₂ of the sixth R_(g) isC(R₅₆R₅₇R₅₈). In some embodiments R₄₂ of the seventh R_(g) isC(R₅₆R₅₇R₅₈). In some embodiments R₄₃ of the eighth R_(g) isC(R₅₆R₅₇R₅₈). In some embodiments R₄₃ of the ninth R_(g) isC(R₅₆R₅₇R₅₈). In some embodiments R₄₂ of the tenth R_(g) isC(R₅₆R₅₇R₅₈).

Z1

In some embodiments R_(h) is C(R₅₉R₆₀), and j is 10, wherein the first,third, fourth, sixth, seventh, ninth, and tenth R_(g) are C(R₄₂R₄₃) andthe second, fifth, and eighth R_(g) are O, wherein R₅₉, R₆₀, R₄₂, R₄₃,R₄₅, R₄₆, and R₄₇ are hydrogen. In some embodiments R_(h) is C(R₅₉R₆₀),j is 10, and R_(f) is C(R₄₅R₄₆R₄₇), wherein the first, third, fourth,sixth, seventh, ninth, and tenth R_(g) are C(R₄₂R₄₃) and the second,fifth, and eighth R_(g) are O, wherein R₅₉, R₆₀, R₄₂, R₄₃, R₄₅, R₄₆, andR₄₇ are hydrogen.

In some embodiments R_(h) is C(R₅₉R₆₀), and j is 4 to 31, wherein thefirst, third, fourth, sixth, seventh, ninth, tenth, twelfth, thirteenth,fifteenth, sixteenth, eighteenth, nineteenth, twenty-first,twenty-second, twenty-fourth, twenty-fifth, twenty-seventh,twenty-eighth, thirtieth, and thirty-first R_(g), if present, areC(R₄₂R₄₃) and the second, fifth, eighth, eleventh, fourteenth,seventeenth, twentieth, twenty-third, twenty-sixth, and twenty-ninth,R_(g), if present, are O, wherein R₅₉, R₆₀, R₄₂, and R₄₃ are hydrogen.In some embodiments R_(h) is C(R₅₉R₆₀), j is 4 to 31, and R_(f) isC(R₄₅R₄₆R₄₇), wherein the first, third, fourth, sixth, seventh, ninth,tenth, twelfth, thirteenth, fifteenth, sixteenth, eighteenth,nineteenth, twenty-first, twenty-second, twenty-fourth, twenty-fifth,twenty-seventh, twenty-eighth, thirtieth, and thirty-first R_(g), ifpresent, are C(R₄₂R₄₃) and the second, fifth, eighth, eleventh,fourteenth, seventeenth, twentieth, twenty-third, twenty-sixth, andtwenty-ninth, R_(g), if present, are O, wherein R₅₉, R₆₀, R₄₂, R₄₃, R₄₅,R₄₆, and R₄₃ are hydrogen.

In some embodiments R_(h) is C(R₅₉R₆₀), and j is 10, wherein the first,third, fourth, sixth, seventh, ninth, and tenth R_(g) are C(R₄₂R₄₃) andthe second, fifth, and eighth R_(g) are O, wherein R₅₉, R₆₀, R₄₂, andR₄₃ are hydrogen, wherein R₄₅, R₄₆, R₄₇, R₄₈, R₄₉, and R₅₀ areindependently, as valency permits, absent, hydrogen, —OH, ═O, —SH, ═N,—NH₂, —NH₃, —CH₃, or —COOH, and wherein R₁₀₀, R₁₀₁, and R₁₀₂ are eachindependently alkyl, phenyl, aryl, or C₃-C₂₀ cyclic. In someembodiments, R₁₀₀, R₁₀₁, and R₁₀₂ are each independently C₁-C₆ alkyl,phenyl, aryl, or C₅-C₆ cyclic.

In some embodiments R_(h) is C(R₅₉R₆₀), j is 10, and R_(f) is hydrogen,C(R₄₅R₄₆R₄₇), OH, SH, S(O)₂, S(O)₃, Si(R₁₀₀R₁₀₁R₁₀₂), or NR₄₈R₄₉R₅₀,wherein the first, third, fourth, sixth, seventh, ninth, and tenth R_(g)are C(R₄₂R₄₃) and the second, fifth, and eighth R_(g) are O, whereinR₅₉, R₆₀, R₄₂, and R₄₃ are hydrogen, wherein R₄₅, R₄₆, R₄₇, R₄₈, R₄₉,and R₅₀ are independently, as valency permits, absent, hydrogen, —OH,═O, —SH, ═N, —NH₂, —NH₃, —CH₃, or —COOH, and wherein R₁₀₀, R₁₀₁, andR₁₀₂ are each independently alkyl, phenyl, aryl, or C₃-C₂₀ cyclic. Insome embodiments, R₁₀₀, R₁₀₁, and R₁₀₂ are each independently C₁-C₆alkyl, phenyl, aryl, or C₅-C₆ cyclic.

In some embodiments R_(h) is C(R₅₉R₆₀), and j is 4 to 31, wherein thefirst, third, fourth, sixth, seventh, ninth, tenth, twelfth, thirteenth,fifteenth, sixteenth, eighteenth, nineteenth, twenty-first,twenty-second, twenty-fourth, twenty-fifth, twenty-seventh,twenty-eighth, thirtieth, and thirty-first R_(g), if present, areC(R₄₂R₄₃) and the second, fifth, eighth, eleventh, fourteenth,seventeenth, twentieth, twenty-third, twenty-sixth, and twenty-ninth,R_(g), if present, are O, wherein R₅₉, R₆₀, R₄₂, and R₄₃ are hydrogen.

In some embodiments R_(h) is C(R₅₉R₆₀), j is 4 to 31, and R_(f) ishydrogen, C(R₄₅R₄₆R₄₇), OH, SH, S(O)₂, S(O)₃, Si(R₁₀₀R₁₀₁R₁₀₂), orNR₄₈R₄₉R₅₀, wherein the first, third, fourth, sixth, seventh, ninth,tenth, twelfth, thirteenth, fifteenth, sixteenth, eighteenth,nineteenth, twenty-first, twenty-second, twenty-fourth, twenty-fifth,twenty-seventh, twenty-eighth, thirtieth, and thirty-first R_(g), ifpresent, are C(R₄₂R₄₃) and the second, fifth, eighth, eleventh,fourteenth, seventeenth, twentieth, twenty-third, twenty-sixth, andtwenty-ninth, R_(g), if present, are O, wherein R₅₉, R₆₀, R₄₂, and R₄₃are hydrogen, wherein R₄₅, R₄₆, R₄₇, R₄₈, R₄₉, and R₅₀ areindependently, as valency permits, absent, hydrogen, —OH, ═O, —SH, ═N,—NH₂, —NH₃, —CH₃, or —COOH, and wherein R₁₀₀, R₁₀₁, and R₁₀₂ are eachindependently alkyl, phenyl, aryl, or C₃-C₂₀ cyclic. In someembodiments, R₁₀₀, R₁₀₁, and R₁₀₂ are each independently C₁-C₆ alkyl,phenyl, aryl, or C₅-C₆ cyclic.

In some embodiments, A, R₆, R₂₄, and R^(b) are independently—R_(h)—(R_(g))_(j), wherein R_(h) is C(R₅₉R₆₀), O, S, S(O)₂, S(O)₃, orNR₆₁; and wherein each R_(g) is independently absent (i.e., j is 0),C(R₄₂R₄₃), O, S, S(O)₂, S(O)₃, or NR₄₄;

wherein j is an integer from 0 to 30,

wherein R₅₉, R₆₀, R₆₁, R₄₂, R₄₃, and R₄₄ are each independently, asvalency permits, absent, hydrogen, ═O, —OR₅₁, —SR₅₂, —NR₅₃R₅₄R₅₅,—C(R₅₆R₅₇R₅₈), or —R_(hx)—(R_(gx))_(jx)—R_(fx),

wherein R₅₁, R₅₂, R₅₃, R₅₄, R₅₅, R₅₆, R₅₇, and R₅₈ are eachindependently, as valency permits, absent, hydrogen, —OH, ═O, —SH, ═NH,—NH₂, —NH₃, —CH₃, or —COOH,

wherein the bond between R_(h) and R_(g), if present, is single, double,or triple depending on the valency, wherein the bond between eachadjacent R_(g) is single, double, or triple depending on the valency;wherein when R_(h) is O, S, S(O)₂, or S(O)₃, the bond between R_(h) andR_(g) is not a double or triple bond; wherein when R_(h) is NR₆₁, thebond between R_(h) and R_(g) is not a triple bond; wherein when R_(g) isO, S, S(O)₂, or S(O)₃, the bond between R_(g) and R_(h) is not a doubleor triple bond; wherein when R_(h) is NR₄₄, the bond between R_(g) andR_(h) is not a triple bond; wherein when R_(h) is O, R_(g) is not O, S,or NR₄₄, and vice versa; wherein when R_(h) is S, R_(g) is not O, S(O)₂,S(O)₃, or NR₄₄, and vice versa; wherein when R_(h) is S(O)₂, R_(g) isnot S, S(O)₂, or S(O)₃, and vice versa; wherein when R_(h) is S(O)₃,R_(g) is not S, S(O)₂, or S(O)₃, and vice versa; and wherein when R_(h)is NR₆₁, R_(g) is not O, or S, and vice versa.

Z2

In some embodiments where A or R₆ is Formula IX, R₁₈, R₁₉, R₂₀, R₂₁,R₂₂, and R₂₃ are carbon, y is 1, R^(e) is R^(b), the ring of Formula IXis aromatic, R₂₄ is —(CR₂₅R₂₅)_(p)—, p is 0 to 10, and R₂₅ areindependently hydrogen or C₁-C₃ alkyl. In some embodiments, R₁₈, R₁₉,R₂₀, R₂₁, R₂₂, and R₂₃ are carbon, y is 1, R^(e) is R^(b), the ring ofFormula IX is aromatic, R₂₄ is —(CR₂₅R₂₅)_(p)—, p is 1, and R₂₅ arehydrogen.

In some embodiments where A or R₆ is Formula IX, R^(e) is at R₂₁. Insome embodiments, R^(e) is at R₁₉. In some embodiments, R^(e) is at R₂₀.In some embodiments, R^(e) is at R₂₂. In some embodiments, R^(e) is atR₂₃. In some embodiments, p is 0. In some embodiments p is 1. In someembodiment p is 2. In some embodiments p is 3. In some embodiment p is4. In some embodiments p is 5. In some embodiments p is 7. In someembodiment p is 8. In some embodiments p is 9. In some embodiments p is10. In some embodiments all R₂₅ are hydrogen. In some embodiments allbut one R₂₅ are hydrogen. In some embodiments all but two R₂₅ arehydrogen. In some embodiments all but three R₂₅ are hydrogen. In someembodiments all but four R₂₅ are hydrogen.

Z1-Y18

In some embodiments, compounds are represented by the general formula:

—X—R₁

wherein X is oxygen, sulfur, or NR₄;

wherein R₄ is -A-B(—C)_(δ) or —R₆—R^(b);

wherein A and R₆ are —R_(h)—(R_(g))_(j),

wherein R_(h) is C(R₅₉R₆₀), and j is 4 to 31, wherein the first, third,fourth, sixth, seventh, ninth, tenth, twelfth, thirteenth, fifteenth,sixteenth, eighteenth, nineteenth, twenty-first, twenty-second,twenty-fourth, twenty-fifth, twenty-seventh, twenty-eighth, thirtieth,and thirty-first R_(g), if present, are C(R₄₂R₄₃) and the second, fifth,eighth, eleventh, fourteenth, seventeenth, twentieth, twenty-third,twenty-sixth, and twenty-ninth, R_(g), if present, are O, wherein R₅₉,R₆₀, R₄₂, and R₄₃ are independently hydrogen or C₁-C₃ alkyl;

wherein B and R^(b) are:

wherein each C, R₈, and R₉ are independently hydrogen or—R_(h)—(R_(g))_(j),

wherein R_(h) is C(R₅₉R₆₀), j is 1 to 15, and each R_(g) is C(R₄₂R₄₃),wherein R₄₂ is ═O and R₄₃ is absent for two R_(g), R₄₂ and R₄₃ arehydrogen for the other R_(g), and R₅₀ and R₆₀ are hydrogen;

wherein R₈ and R₀ are not both hydrogen, wherein at least one of C isnot hydrogen.

In some embodiments where A or R₆ is —R_(h)—(R_(g))_(j), R_(h) isC(R₅₉R₆₀), and j is 4 to 31, wherein the first, third, fourth, sixth,seventh, ninth, tenth, twelfth, thirteenth, fifteenth, sixteenth,eighteenth, nineteenth, twenty-first, twenty-second, twenty-fourth,twenty-fifth, twenty-seventh, twenty-eighth, thirtieth, and thirty-firstR_(g), if present, are C(R₄₂R₄₃) and the second, fifth, eighth,eleventh, fourteenth, seventeenth, twentieth, twenty-third,twenty-sixth, and twenty-ninth, R_(g), if present, are O, wherein R₅₉,R₆₀, R₄₂, and RB are hydrogen or C₁-C₃ alkyl. In some embodiments R₅₉and R₆₀ are hydrogen. In some embodiments R₅₉ is hydrogen and R₆₀ isC₁-C₃ alkyl. In some embodiments R₅₉ and R₆₀ are C₁-C₃ alkyl. In someembodiments all R₄₂ are hydrogen. In some embodiments all but one RB arehydrogen. In some embodiments all but two RB are hydrogen. In someembodiments all but three RB are hydrogen. In some embodiments all butfour R₄₂ are hydrogen. In some embodiments all but five RB are hydrogen.In some embodiments all but six RB are hydrogen. In some embodiments allbut seven R₄₂ are hydrogen. In some embodiments all but eight RB arehydrogen. In some embodiments all but nine RB are hydrogen. In someembodiments all but ten R₄₂ are hydrogen. In some embodiments all buteleven RB are hydrogen. In some embodiments all but twelve R₄₂ arehydrogen. In some embodiments all R₄₃ are hydrogen. In some embodimentsall but one RB are hydrogen. In some embodiments all but two RB arehydrogen. In some embodiments all but three RB are hydrogen. In someembodiments all but four R₄₃ are hydrogen. In some embodiments all butfive R₄₃ are hydrogen. In some embodiments all but six RB are hydrogen.In some embodiments all but seven RB are hydrogen. In some embodimentsall but eight R₄₃ are hydrogen. In some embodiments all but nine R₄₃ arehydrogen. In some embodiments all but ten R₄₃ are hydrogen. In someembodiments all but eleven R₄₃ are hydrogen. In some embodiments all buttwelve R₄₃ are hydrogen.

In some embodiments where A or R₆ is —R_(h)—(R_(g))_(j), R_(h) isC(R₅₉R₆₀), and j is 10, wherein the first, third, fourth, sixth,seventh, ninth, and tenth R_(g) are C(R₄₂R₄₃) and the second, fifth, andeighth R_(g) are O, and wherein R₅₉, R₆₀, R₄₂, and R₄₃ are hydrogen.

In some embodiments R_(h) is C(R₅₉R₆₀), and j is 0, wherein R₅₉ is ═O,and R₆₀ is absent. In some embodiments R_(h) is C(R₅₉R₆₀), j is 0 to 10,and each R_(g) is C(R₄₂R₄₃), wherein R₅₉ is ═O, R₆₀ is absent, and R₄₂and R₄₃ are hydrogen. In some embodiments j is 1. In some embodiment jis 2. In some embodiments j is 3. In some embodiment j is 4. In someembodiments j is 5. In some embodiments j is 7. In some embodiment j is8. In some embodiments j is 9. In some embodiments j is 10.

In some embodiments R_(h) is C(R₅₉R₆₀), j is 1 to 10, and each R_(g) isC(R₄₂R₄₃), wherein R₄₂ is ═O and R₄₃ is absent for one R_(g), R₄₂ andR₄₃ are hydrogen for the other R_(g), and R₅₉ and R₆₀ are hydrogen. Insome embodiments R₄₃ is ═O and R₄₃ is absent for the last R_(g). In someembodiments R₄₃ is ═O and R₄₃ is absent for the penultimate R_(g). Insome embodiments R₄₃ is ═O and R₄₃ is absent for the antepenultimateR_(g). In some embodiments R₄₃ is ═O and R₄₃ is absent for the fourthfrom the last R_(g). In some embodiments R₄₃ is ═O and R₄₃ is absent forthe fifth from the last R_(g). In some embodiments R₄₃ is ═O and R₄₃ isabsent for the first R_(g). In some embodiments R₄₃ is ═O and R₄₃ isabsent for the second R_(g). In some embodiments R₄₃ is ═O and R₄₃ isabsent for the third R_(g). In some embodiments R₄₂ is ═O and R₄₃ isabsent for the fourth R_(g). In some embodiments R₄₃ is ═O and R₄₃ isabsent for the fifth R_(g).

In some embodiments R_(h) is C(R₅₉R₆₀), j is 1 to 15, and each R_(g) isC(R₄₂R₄₃), wherein R₄₃ is ═O and R₄₃ is absent for two R_(g), R₄₂ andR₄₃ are hydrogen for the other R_(g), and R₅₉ and R₆₀ are hydrogen. Insome embodiments R₄₃ is ═O and R₄₃ is absent the first and third R_(g).In some embodiments R₄₃ is ═O and R₄₃ is absent the first and fourthR_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent the first andfifth R_(g). In some embodiments R₄₃ is ═O and R₄₃ is absent the firstand sixth R_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent thefirst and seventh R_(g). In some embodiments R₄₃ is ═O and R₄₃ is absentthe first and eighth R_(g). In some embodiments R₄₃ is ═O and R₄₃ isabsent the first and ninth R_(g). In some embodiments R₄₃ is ═O and R₄₃is absent the first and tenth R_(g). In some embodiments R₄₂ is ═O andR₄₃ is absent the first and eleventh R_(g). In some embodiments R₄₃ is═O and R₄₃ is absent the first and twelfth R_(g). In some embodimentsR₄₂ is ═O and R₄₃ is absent the first and thirteenth R_(g). In someembodiments R₄₂ is ═O and R₄₃ is absent the first and fourteenth R_(g).In some embodiments R₄₃ is ═O and R₄₃ is absent the first and fifteenthR_(g). In some embodiments R₄₃ is ═O and R₄₃ is absent the second andfourth R_(g). In some embodiments R₄₃ is ═O and R₄₃ is absent the secondand fifth R_(g). In some embodiments R₄₃ is ═O and R₄₃ is absent thesecond and sixth R_(g). In some embodiments R₄₃ is ═O and R₄₃ is absentthe second and seventh R_(g). In some embodiments R₄₃ is ═O and R₄₃ isabsent the second and eighth R_(g). In some embodiments R₄₃ is ═O andR₄₃ is absent the second and ninth R_(g). In some embodiments R₄₂ is ═Oand R₄₃ is absent the second and tenth R_(g). In some embodiments R₄₂ is═O and R₄₃ is absent the second and eleventh R_(g). In some embodimentsR₄₃ is ═O and R₄₃ is absent the second and twelfth R_(g). In someembodiments R₄₂ is ═O and R₄₃ is absent the second and thirteenth R_(g).In some embodiments R₄₂ is ═O and R₄₃ is absent the second andfourteenth R_(g). In some embodiments R₄₃ is ═O and R₄₃ is absent thesecond and fifteenth R_(g). In some embodiments R₄₂ is ═O and R₄₃ isabsent the third and fifth R_(g). In some embodiments R₄₃ is ═O and R₄₃is absent the third and sixth R_(g). In some embodiments R₄₃ is ═O andR₄₃ is absent the third and seventh R_(g). In some embodiments R₄₂ is ═Oand R₄₃ is absent the third and eighth R_(g). In some embodiments R₄₂ is═O and R₄₃ is absent the third and ninth R_(g). In some embodiments R₄₃is ═O and R₄₃ is absent the third and tenth R_(g). In some embodimentsR₄₂ is ═O and R₄₃ is absent the third and eleventh R_(g). In someembodiments R₄₂ is ═O and R₄₃ is absent the third and twelfth R_(g). Insome embodiments R₄₂ is ═O and R₄₃ is absent the third and thirteenthR_(g). In some embodiments R₄₃ is ═O and R₄₃ is absent the third andfourteenth R_(g). In some embodiments R₄₃ is ═O and R₄₃ is absent thethird and fifteenth R_(g). In some embodiments R₄₃ is ═O and R₄₃ isabsent the fourth and sixth R_(g). In some embodiments R₄₂ is ═O and R₄₃is absent the fourth and seventh R_(g). In some embodiments R₄₂ is ═Oand R₄₃ is absent the fourth and eighth R_(g). In some embodiments R₄₂is ═O and R₄₃ is absent the fourth and ninth R_(g). In some embodimentsR₄₂ is ═O and R₄₃ is absent the fourth and tenth R_(g). In someembodiments R₄₂ is ═O and R₄₃ is absent the fourth and eleventh R_(g).In some embodiments R₄₂ is ═O and R₄₃ is absent the fourth and twelfthR_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent the fourth andthirteenth R_(g). In some embodiments R₄₃ is ═O and R₄₃ is absent thefourth and fourteenth R_(g). In some embodiments R₄₃ is ═O and R₄₃ isabsent the fourth and fifteenth R_(g). In some embodiments R₄₃ is ═O andR₄₃ is absent the fifth and seventh R_(g). In some embodiments R₄₂ is ═Oand R₄₃ is absent the fifth and eighth R_(g). In some embodiments R₄₂ is═O and R₄₃ is absent the fifth and ninth R_(g). In some embodiments R₄₂is ═O and R₄₃ is absent the fifth and tenth R_(g). In some embodimentsR₄₂ is ═O and R₄₃ is absent the fifth and eleventh R_(g). In someembodiments R₄₂ is ═O and R₄₃ is absent the fifth and twelfth R_(g). Insome embodiments R₄₂ is ═O and R₄₃ is absent the fifth and thirteenthR_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent the fifth andfourteenth R_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent thefifth and fifteenth R_(g). In some embodiments R₄₂ is ═O and R₄₃ isabsent the sixth and eighth R_(g). In some embodiments R₄₂ is ═O and R₄₃is absent the sixth and ninth R_(g). In some embodiments R₄₂ is ═O andR₄₃ is absent the sixth and tenth R_(g). In some embodiments R₄₂ is ═Oand R₄₃ is absent the sixth and eleventh R_(g). In some embodiments R₄₂is ═O and R₄₃ is absent the sixth and twelfth R_(g). In some embodimentsR₄₂ is ═O and R₄₃ is absent the sixth and thirteenth R_(g). In someembodiments R₄₂ is ═O and R₄₃ is absent the sixth and fourteenth R_(g).In some embodiments R₄₂ is ═O and R₄₃ is absent the sixth and fifteenthR_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent the seventh andninth R_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent the seventhand tenth R_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent theseventh and eleventh R_(g). In some embodiments R₄₂ is ═O and R₄₃ isabsent the seventh and twelfth R_(g). In some embodiments R₄₂ is ═O andR₄₃ is absent the seventh and thirteenth R_(g). In some embodiments R₄₂is ═O and R₄₃ is absent the seventh and fourteenth R_(g). In someembodiments R₄₂ is ═O and R₄₃ is absent the seventh and fifteenth R_(g).In some embodiments R₄₂ is ═O and R₄₃ is absent the eighth and tenthR_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent the eighth andeleventh R_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent theeighth and twelfth R_(g). In some embodiments R₄₂ is ═O and R₄₃ isabsent the eighth and thirteenth R_(g). In some embodiments R₄₂ is ═Oand R₄₃ is absent the eighth and fourteenth R_(g). In some embodimentsR₄₂ is ═O and R₄₃ is absent the eighth and fifteenth R_(g). In someembodiments R₄₂ is ═O and R₄₃ is absent the ninth and eleventh R_(g). Insome embodiments R₄₂ is ═O and R₄₃ is absent the ninth and twelfthR_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent the ninth andthirteenth R_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent theninth and fourteenth R_(g). In some embodiments R₄₂ is ═O and R₄₃ isabsent the ninth and fifteenth R_(g). In some embodiments R₄₂ is ═O andR₄₃ is absent the tenth and twelfth R_(g). In some embodiments R₄₂ is ═Oand R₄₃ is absent the tenth and thirteenth R_(g). In some embodimentsR₄₂ is ═O and R₄₃ is absent the tenth and fourteenth R_(g). In someembodiments R₄₂ is ═O and R₄₃ is absent the tenth and fifteenth R_(g).In some embodiments R₄₂ is ═O and R₄₃ is absent the eleventh andthirteenth R_(g). In some embodiments R₄₂ is ═O and R₄₃ is absent theeleventh and fourteenth R_(g). In some embodiments R₄₂ is ═O and R₄₃ isabsent the eleventh and fifteenth R_(g). In some embodiments R₄₃ is ═Oand R₄₃ is absent the twelfth and fourteenth R_(g). In some embodimentsR₄₃ is ═O and R₄₃ is absent the twelfth and fifteenth R_(g). In someembodiments the thirteenth and fifteenth R_(g).

Z1-Y12

In some embodiments, compounds are represented by the general formula:

—X—R₁

wherein X is oxygen, sulfur, or NR₄;

wherein R₄ is -A-B(—C)_(δ) or —R₆—R^(b);

wherein A and R₆ are —R_(h)—(R_(g))_(j),

wherein R_(h) is C(R₅₉R₆₀), and j is 4 to 31, wherein the first, third,fourth, sixth, seventh, ninth, tenth, twelfth, thirteenth, fifteenth,sixteenth, eighteenth, nineteenth, twenty-first, twenty-second,twenty-fourth, twenty-fifth, twenty-seventh, twenty-eighth, thirtieth,and thirty-first R_(g), if present, are C(R₄₂R₄₃) and the second, fifth,eighth, eleventh, fourteenth, seventeenth, twentieth, twenty-third,twenty-sixth, and twenty-ninth, R_(g), if present, are O, wherein R₅₉,R₆₀, R₄₂, and R₄₃ are independently hydrogen or C₁-C₃ alkyl;

wherein B and R^(b) are:

wherein each C, R₈, and R₀ are independently hydrogen or

wherein for C, R₈, and R₀, R₁₈ is carbon, one or two of nonadjacent R₁₉,R₂₀, R₂₁, R₂₂, and R₂₃ are O, the rest of R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃are carbon, y is 0 to 3, R^(e) are independently C₁-C₃ alkyl, C₁-C₃alkoxy, amino, C₁-C₃ alkylamino, C₁-C₃ dialkylamino, hydroxy, C₁-C₃alkenyl, or C₁-C₃ alkynyl, the ring of Formula IX has no double bonds,R₂₄ is —(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, p is 0 to 5, q is 0 to 5,R₂₅ are independently hydrogen or C₁-C₃ alkyl, and X_(b) is O;

wherein R₈ and R₀ are not both hydrogen, wherein at least one of C isnot hydrogen.

In some embodiments where A or R₆ is —R_(h)—(R_(g))_(j), R_(h) isC(R₅₉R₆₀), and j is 4 to 31, wherein the first, third, fourth, sixth,seventh, ninth, tenth, twelfth, thirteenth, fifteenth, sixteenth,eighteenth, nineteenth, twenty-first, twenty-second, twenty-fourth,twenty-fifth, twenty-seventh, twenty-eighth, thirtieth, and thirty-firstR_(g), if present, are C(R₄₂R₄₃) and the second, fifth, eighth,eleventh, fourteenth, seventeenth, twentieth, twenty-third,twenty-sixth, and twenty-ninth, R_(g), if present, are O, wherein R₅₉,R₆₀, R₄₂, and R₄₃ are hydrogen or C₁-C₃ alkyl. In some embodiments R₅₉and R₆₀ are hydrogen. In some embodiments R₅₉ is hydrogen and R₆₀ isC₁-C₃ alkyl. In some embodiments R₅₉ and Rbo are C₁-C₃ alkyl. In someembodiments all R₄₃ are hydrogen. In some embodiments all but one R₄₃are hydrogen. In some embodiments all but two R₄₃ are hydrogen. In someembodiments all but three R₄₃ are hydrogen. In some embodiments all butfour R₄₂ are hydrogen. In some embodiments all but five R₄₃ arehydrogen. In some embodiments all but six R₄₃ are hydrogen. In someembodiments all but seven R₄₂ are hydrogen. In some embodiments all buteight R₄₃ are hydrogen. In some embodiments all but nine R₄₃ arehydrogen. In some embodiments all but ten R₄₂ are hydrogen. In someembodiments all but eleven R₄₃ are hydrogen. In some embodiments all buttwelve R₄₂ are hydrogen. In some embodiments all R₄₃ are hydrogen. Insome embodiments all but one R₄₃ are hydrogen. In some embodiments allbut two R₄₃ are hydrogen. In some embodiments all but three R₄₃ arehydrogen. In some embodiments all but four R₄₃ are hydrogen. In someembodiments all but five R₄₃ are hydrogen. In some embodiments all butsix R₄₃ are hydrogen. In some embodiments all but seven R₄₃ arehydrogen. In some embodiments all but eight R₄₃ are hydrogen. In someembodiments all but nine R₄₃ are hydrogen. In some embodiments all butten R₄₃ are hydrogen. In some embodiments all but eleven R₄₃ arehydrogen. In some embodiments all but twelve R₄₃ are hydrogen.

In some embodiments where A or R₆ is —R_(h)—(R_(g))_(j), R_(h) isC(R₅₉R₆₀), and j is 10, wherein the first, third, fourth, sixth,seventh, ninth, and tenth R_(g) are C(R₄₂R₄₃) and the second, fifth, andeighth R_(g) are O, and wherein R₅₉, R₆₀, R₄₂, and R₄₃ are hydrogen.

In some embodiments where one or more of C, R₈, and R₀ are Formula IX,in such C, R₈, and R₉: R₁₈ is carbon, one or two of nonadjacent R₁₉,R₂₀, R₂₁, R₂₂, and R₂₃ are O, the rest of R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃are carbon, y is 0 to 3, R^(e) are independently C₁-C₃ alkyl, C₁-C₃alkoxy, amino, C₁-C₃ alkylamino, C₁-C₃ dialkylamino, hydroxy, C₁-C₃alkenyl, or C₁-C₃ alkynyl, the ring of Formula IX has no double bonds,R₂₄ is —(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, p is 0 to 5, q is 0 to 5,R₂₅ are independently hydrogen or C₁-C₃ alkyl, and X_(b) is O.

In some embodiments where one or more of C, R₈, and R₀ are Formula IX,in such C, R₈, and R₀: R₁₈ is carbon, one or two of nonadjacent R₁₉,R₂₀, R₂₁, R₂₂, and R₂₃ are O, the rest of R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃are carbon, y is 0 to 3, R^(e) are independently C₁-C₃ alkyl, C₁-C₃alkoxy, amino, C₁-C₃ alkylamino, C₁-C₃ dialkylamino, hydroxy, C₁-C₃alkenyl, or C₁-C₃ alkynyl, the ring of Formula IX has no double bonds,R₂₄ is —(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, p is 0 to 5, q is 0 to 5,R₂₅ are independently hydrogen or C₁-C₃ alkyl, and X_(b) is O. In someembodiments R₈ is hydrogen. In some embodiments, R₀ is hydrogen. In someembodiments, R₁₉ is O and R₂₀, R₂₁, R₂₂, and R₂₃ are carbon. In someembodiments, R₂₀ is O and R₁₉, R₂₁, R₂₂, and R₂₃ are carbon. In someembodiments, R₂₁ is O and R₁₉, R₂₀, R₂₂, and R₂₃ are carbon. In someembodiments, R₂₂ is O and R₁₉, R₂₀, R₂₁, and R₂₃ are carbon. In someembodiments, R₂₃ is O and R₁₉, R₂₀, R₂₁, and R₂₂ are carbon. In someembodiments, R₁₉ and R₂₁ are O. In some embodiments, R₁₉ and R₂₂ are O.In some embodiments, R₁₉ and R₂₃ are O. In some embodiments, R₂₀ and R₂₂are O. In some embodiments, R₂₀ and R₂₃ are O. In some embodiments, R₂₁and R₂₃ are O. In some embodiments y is 0. In some embodiments y is 1.In some embodiments y is 2. In some embodiments y is 3. In someembodiments R^(e) is independently methyl, ethyl, methoxy, ethoxy, aminomethyl, amino ethyl, hydroxyl, or amino. In some embodiments, p is 0. Insome embodiments p is 1. In some embodiment p is 2. In some embodimentsp is 3. In some embodiments p is 4. In some embodiments p is 5. In someembodiments, q is 0. In some embodiments q is 1. In some embodiment q is2. In some embodiments q is 3. In some embodiments q is 4. In someembodiments q is 5. In some embodiments all R₂₅ are hydrogen. In someembodiments all but one R₂₅ are hydrogen. In some embodiments all buttwo R₂₅ are hydrogen. In some embodiments all but three R₂₅ arehydrogen. In some embodiments all but four R₂₅ are hydrogen.

In some embodiments where at least one C is Formula IX, R₈ is hydrogen,and R₉ is Formula IX, in such C and R₉: R₁₉ is O, R₁₈, R₂₀, R₂₁, R₂₂,and R₂₃ are carbon, y is 0, the ring of Formula IX has no double bonds,R₂₄ is —(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, p is 0, q is 1, both R₂₅ arehydrogen, and X_(b) is O.

Z1-Y17

In some embodiments, compounds are represented by the general formula:

—X—R₁

wherein X is oxygen, sulfur, or NR₄;

wherein R₄ is -A-B(—C)_(δ) or —R₆—R^(b);

wherein A and Rb are —R_(h)—(R_(g))_(j),

wherein R_(h) is C(R₅₉R₆₀), and j is 4 to 31, wherein the first, third,fourth, sixth, seventh, ninth, tenth, twelfth, thirteenth, fifteenth,sixteenth, eighteenth, nineteenth, twenty-first, twenty-second,twenty-fourth, twenty-fifth, twenty-seventh, twenty-eighth, thirtieth,and thirty-first R_(g), if present, are C(R₄₂R₄₃) and the second, fifth,eighth, eleventh, fourteenth, seventeenth, twentieth, twenty-third,twenty-sixth, and twenty-ninth, R_(g), if present, are O, wherein R₅₉,R₆₀, R₄₂, and R₄₃ are independently hydrogen or C₁-C₃ alkyl;

wherein B and R^(b) are:

wherein each C, R₈, and R₀ are independently hydrogen or

wherein for C, R₈, and R₉, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are carbon,y is 0 to 3, R^(e) are independently C₁-C₃ alkyl, C₁-C₃ alkoxy, amino,C₁-C₃ alkylamino, C₁-C₃ dialkylamino, hydroxy, C₁-C₃ alkenyl, or C₁-C₃alkynyl, the ring of Formula IX is aromatic, R₂₄ is —(CR₂₅R₂₅)_(p)—, andp is 0;

wherein R₈ and R₀ are not both hydrogen, wherein at least one of C isnot hydrogen.

In some embodiments where A or R₆ is —R_(h)—(R_(g))_(j), R_(h) isC(R₅₉R₆₀), and j is 4 to 31, wherein the first, third, fourth, sixth,seventh, ninth, tenth, twelfth, thirteenth, fifteenth, sixteenth,eighteenth, nineteenth, twenty-first, twenty-second, twenty-fourth,twenty-fifth, twenty-seventh, twenty-eighth, thirtieth, and thirty-firstR_(g), if present, are C(R₄₂R₄₃) and the second, fifth, eighth,eleventh, fourteenth, seventeenth, twentieth, twenty-third,twenty-sixth, and twenty-ninth, R_(g), if present, are O, wherein R₅₉,R₆₀, R₄₂, and R₄₃ are hydrogen or C₁-C₃ alkyl. In some embodiments R₅₀and R₆₀ are hydrogen. In some embodiments R₅₉ is hydrogen and R₆₀ isC₁-C₃ alkyl. In some embodiments R₅₉ and Reo are C₁-C₃ alkyl. In someembodiments all R₄₂ are hydrogen. In some embodiments all but one R₄₃are hydrogen. In some embodiments all but two R₄₃ are hydrogen. In someembodiments all but three R₄₃ are hydrogen. In some embodiments all butfour R₄₂ are hydrogen. In some embodiments all but five R₄₃ arehydrogen. In some embodiments all but six R₄₃ are hydrogen. In someembodiments all but seven R₄₂ are hydrogen. In some embodiments all buteight R₄₃ are hydrogen. In some embodiments all but nine R₄₃ arehydrogen. In some embodiments all but ten R₄₂ are hydrogen. In someembodiments all but eleven R₄₃ are hydrogen. In some embodiments all buttwelve R₄₂ are hydrogen. In some embodiments all R₄₃ are hydrogen. Insome embodiments all but one R₄₃ are hydrogen. In some embodiments allbut two R₄₃ are hydrogen. In some embodiments all but three R₄₃ arehydrogen. In some embodiments all but four R₄₃ are hydrogen. In someembodiments all but five R₄₃ are hydrogen. In some embodiments all butsix R₄₃ are hydrogen. In some embodiments all but seven R₄₃ arehydrogen. In some embodiments all but eight R₄₃ are hydrogen. In someembodiments all but nine R₄₃ are hydrogen. In some embodiments all butten R₄₃ are hydrogen. In some embodiments all but eleven R₄₃ arehydrogen. In some embodiments all but twelve R₄₃ are hydrogen.

In some embodiments where A or R₆ is —R_(h)—(R_(g))_(j), R_(h) isC(R₅₉R₆₀), and j is 10, wherein the first, third, fourth, sixth,seventh, ninth, and tenth R_(g) are C(R₄₂R₄₃) and the second, fifth, andeighth R_(g) are O, and wherein R₅₉, R₆₀, R₄₂, and R₄₃ are hydrogen.

In some embodiments, in Formula IX, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ arecarbon, y is 0, the ring of Formula IX is aromatic, R₂₄ is—(CR₂₅R₂₅)_(p)—, and p is 0.

In some embodiments, in Formula IX, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ arecarbon, y is 1, R^(e) are independently C₁-C₃ alkyl, C₁-C₃ alkoxy,amino, C₁-C₃ alkylamino, C₁-C₃ dialkylamino, hydroxy, C₁-C₃ alkenyl, orC₁-C₃ alkynyl, the ring of Formula IX is aromatic, R₂₄ is—(CR₂₅R₂₅)_(p)—, and p is 0.

Z1-Y1

In some embodiments, compounds are represented by the general formula:

—X—R₁

wherein X is oxygen, sulfur, or NR₄;

wherein R₄ is -A-B(—C)_(δ) or —R₆—R^(b);

wherein A and R₆ are —R_(h)—(R_(g))_(j),

wherein R_(h) is C(R₅₉R₆₀), and j is 4 to 31, wherein the first, third,fourth, sixth, seventh, ninth, tenth, twelfth, thirteenth, fifteenth,sixteenth, eighteenth, nineteenth, twenty-first, twenty-second,twenty-fourth, twenty-fifth, twenty-seventh, twenty-eighth, thirtieth,and thirty-first R_(g), if present, are C(R₄₂R₄₃) and the second, fifth,eighth, eleventh, fourteenth, seventeenth, twentieth, twenty-third,twenty-sixth, and twenty-ninth, R_(g), if present, are O, wherein R₅₉,R₆₀, R₄₂, and R₄₃ are independently hydrogen or C₁-C₃ alkyl;

wherein B and R^(b) are:

wherein each C, R₈, and R₀ are independently hydrogen or

wherein for C, R₈, and R₉, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are carbon,y is 1, R^(e) is hydroxy, C₁-C₃ alkyl, C₁-C₃ alkoxy, amino, C₁-C₃alkylamino, C₁-C₃ dialkylamino, hydroxy, C₁-C₃ alkenyl, or C₁-C₃alkynyl, the ring of Formula IX has no double bonds, R₂₄ is—(CR₂₅R₂₅)_(p)—, and p is 0;

wherein R₈ and R₀ are not both hydrogen, wherein at least one of C isnot hydrogen.

In some embodiments where A or R₆ is —R_(h)—(R_(g))_(j), R_(h) isC(R₅₉R₆₀), and j is 4 to 31, wherein the first, third, fourth, sixth,seventh, ninth, tenth, twelfth, thirteenth, fifteenth, sixteenth,eighteenth, nineteenth, twenty-first, twenty-second, twenty-fourth,twenty-fifth, twenty-seventh, twenty-eighth, thirtieth, and thirty-firstR_(g), if present, are C(R₄₂R₄₃) and the second, fifth, eighth,eleventh, fourteenth, seventeenth, twentieth, twenty-third,twenty-sixth, and twenty-ninth, R_(g), if present, are O, wherein R₅₉,R₆₀, R₄₂, and R₄₃ are hydrogen or C₁-C₃ alkyl. In some embodiments R₅₀and R₆₀ are hydrogen. In some embodiments R₅₉ is hydrogen and R₆₀ isC₁-C₃ alkyl. In some embodiments R₅₉ and Reo are C₁-C₃ alkyl. In someembodiments all R₄₂ are hydrogen. In some embodiments all but one R₄₃are hydrogen. In some embodiments all but two R₄₃ are hydrogen. In someembodiments all but three R₄₃ are hydrogen. In some embodiments all butfour R₄₂ are hydrogen. In some embodiments all but five R₄₃ arehydrogen. In some embodiments all but six R₄₃ are hydrogen. In someembodiments all but seven R₄₂ are hydrogen. In some embodiments all buteight R₄₃ are hydrogen. In some embodiments all but nine R₄₃ arehydrogen. In some embodiments all but ten R₄₂ are hydrogen. In someembodiments all but eleven R₄₃ are hydrogen. In some embodiments all buttwelve R₄₂ are hydrogen. In some embodiments all R₄₃ are hydrogen. Insome embodiments all but one R₄₃ are hydrogen. In some embodiments allbut two R₄₃ are hydrogen. In some embodiments all but three R₄₃ arehydrogen. In some embodiments all but four R₄₃ are hydrogen. In someembodiments all but five R₄₃ are hydrogen. In some embodiments all butsix R₄₃ are hydrogen. In some embodiments all but seven R₄₃ arehydrogen. In some embodiments all but eight R₄₃ are hydrogen. In someembodiments all but nine R₄₃ are hydrogen. In some embodiments all butten R₄₃ are hydrogen. In some embodiments all but eleven R₄₃ arehydrogen. In some embodiments all but twelve R₄₃ are hydrogen.

In some embodiments where A or R₆ is —R_(h)—(R_(g))_(j), R_(h) isC(R₅₉R₆₀), and j is 10, wherein the first, third, fourth, sixth,seventh, ninth, and tenth R_(g) are C(R₄₂R₄₃) and the second, fifth, andeighth R_(g) are O, and wherein R₅₉, R₆₀, R₄₂, and R₄₃ are hydrogen.

In some embodiments, in Formula IX, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ arecarbon, y is 1, R^(e) is hydroxy, the ring of Formula IX has no doublebonds, R₂₄ is —(CR₂₅R₂₅)_(p)—, and p is 0. In some embodiments, R^(e) isat R₂₁. In some embodiments, R^(e) is at R₁₉. In some embodiments, R^(e)is at R₂₀. In some embodiments, R^(e) is at R₂₂. In some embodiments,R^(e) is at R₂₃.

Z1-Y9

In some embodiments, compounds are represented by the general formula:

—X—R₁

wherein X is oxygen, sulfur, or NR₄;

wherein R₁ is -A-B(—C)_(δ) or —R₆—R^(b);

wherein A and R₆ are —R_(h)—(R_(g))_(j),

wherein R_(h) is C(R₅₉R₆₀), and j is 4 to 31, wherein the first, third,fourth, sixth, seventh, ninth, tenth, twelfth, thirteenth, fifteenth,sixteenth, eighteenth, nineteenth, twenty-first, twenty-second,twenty-fourth, twenty-fifth, twenty-seventh, twenty-eighth, thirtieth,and thirty-first R_(g), if present, are C(R₄₂R₄₃) and the second, fifth,eighth, eleventh, fourteenth, seventeenth, twentieth, twenty-third,twenty-sixth, and twenty-ninth, R_(g), if present, are O, wherein R₅₉,R₆₀, R₄₂, and R₄₃ are independently hydrogen or C₁-C₃ alkyl;

wherein B and R^(b) are:

wherein C and R₉ are independently hydrogen or

wherein C and R₈, independently hydrogen or —R_(h)—(R_(g))_(j),

wherein for C and R₉, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are carbon, y is0, the ring of Formula IX is aromatic, R₂₄ is —(CR₂₅R₂₅)_(p)—, and p is0; wherein R_(h) is C(R₅₉R₆₀), and j is 0, wherein R₅₉ is ═O and R₆₀ is—OH. In some embodiments R_(h) is absent, j is 0 to 10, and each R_(g)is C(R₄₂R₄₃), wherein R₄₂ and R₄₃ are hydrogen;

wherein R₈ and R₉ are not both hydrogen, wherein at least one of C isnot hydrogen.

In some embodiments where A or R₆ is —R_(h)—(R_(g))_(j), R_(h) isC(R₅₉R₆₀), and j is 4 to 31, wherein the first, third, fourth, sixth,seventh, ninth, tenth, twelfth, thirteenth, fifteenth, sixteenth,eighteenth, nineteenth, twenty-first, twenty-second, twenty-fourth,twenty-fifth, twenty-seventh, twenty-eighth, thirtieth, and thirty-firstR_(g), if present, are C(R₄₂R₄₃) and the second, fifth, eighth,eleventh, fourteenth, seventeenth, twentieth, twenty-third,twenty-sixth, and twenty-ninth, R_(g), if present, are O, wherein R₅₉,R₆₀, R₄₂, and R₄₃ are hydrogen or C₁-C₃ alkyl. In some embodiments R₅₉and R₆₀ are hydrogen. In some embodiments R₅₉ is hydrogen and R₆₀ isC₁-C₃ alkyl. In some embodiments R₅₉ and R₆₀ are C₁-C₃ alkyl. In someembodiments all R₄₃ are hydrogen. In some embodiments all but one R₄₃are hydrogen. In some embodiments all but two R₄₃ are hydrogen. In someembodiments all but three R₄₃ are hydrogen. In some embodiments all butfour R₄₂ are hydrogen. In some embodiments all but five R₄₃ arehydrogen. In some embodiments all but six R₄₃ are hydrogen. In someembodiments all but seven R₄₂ are hydrogen. In some embodiments all buteight R₄₃ are hydrogen. In some embodiments all but nine R₄₃ arehydrogen. In some embodiments all but ten R₄₂ are hydrogen. In someembodiments all but eleven R₄₂ are hydrogen. In some embodiments all buttwelve R₄₂ are hydrogen. In some embodiments all R₄₃ are hydrogen. Insome embodiments all but one R₄₃ are hydrogen. In some embodiments allbut two R₄₃ are hydrogen. In some embodiments all but three R₄₃ arehydrogen. In some embodiments all but four R₄₃ are hydrogen. In someembodiments all but five R₄₃ are hydrogen. In some embodiments all butsix R₄₃ are hydrogen. In some embodiments all but seven R₄₃ arehydrogen. In some embodiments all but eight R₄₃ are hydrogen. In someembodiments all but nine R₄₃ are hydrogen. In some embodiments all butten R₄₃ are hydrogen. In some embodiments all but eleven R₄₃ arehydrogen. In some embodiments all but twelve R₄₃ are hydrogen.

In some embodiments where A or R₆ is —R_(h)—(R_(g))_(j), R_(h) isC(R₅₉R₆₀), and j is 10, wherein the first, third, fourth, sixth,seventh, ninth, and tenth R_(g) are C(R₄₂R₄₃) and the second, fifth, andeighth R_(g) are O, and wherein R₅₉, R₆₀, R₄₂, and R₄₃ are hydrogen.

In some embodiments, one C or R₈ is —R_(h)—(R_(g))_(j), and one C or R₉is, wherein in Formula IX, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are carbon,y is 0, the ring of Formula IX is aromatic, R₂₄ is —(CR₂₅R₂₅)_(p)—, andp is 0, wherein R_(h) is C(R₅₉R₆₀), and j is 0, wherein R₅₉ is ═O andR₆₀ is —OH. In some embodiments R_(h) is absent, j is 0 to 10, and eachR_(g) is C(R₄₂R₄₃), wherein R₄₂ and R₄₃ are hydrogen.

Z1-Y2

In some embodiments, compounds are represented by the general formula:

—X—R₁

wherein X is oxygen, sulfur, or NR₄;

wherein R₁ is -A-B(—C)_(δ) or —R₆—R^(b);

wherein A and R₆ are —R_(h)—(R_(g))_(j),

wherein R_(h) is C(R₅₉R₆₀), and j is 4 to 31, wherein the first, third,fourth, sixth, seventh, ninth, tenth, twelfth, thirteenth, fifteenth,sixteenth, eighteenth, nineteenth, twenty-first, twenty-second,twenty-fourth, twenty-fifth, twenty-seventh, twenty-eighth, thirtieth,and thirty-first R_(g), if present, are C(R₄₂R₄₃) and the second, fifth,eighth, eleventh, fourteenth, seventeenth, twentieth, twenty-third,twenty-sixth, and twenty-ninth, R_(g), if present, are O, wherein R₅₉,R₆₀, R₄₂, and R₄₃ are independently hydrogen or C₁-C₃ alkyl;

wherein B and R^(b) are:

wherein each C, R₈, and R₀ are independently hydrogen or

wherein for C, R₈, and R₉, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are carbon,y is 1, R^(e) is —O—CH₃, the ring of Formula IX is aromatic, R₂₄ is—(CR₂₅R₂₅)_(p)—, and p is 0. In some embodiments, R^(e) is at R₂₁;

wherein R₈ and R₉ are not both hydrogen, wherein at least one of C isnot hydrogen.

In some embodiments where A or R₆ is —R_(h)—(R_(g))_(j), R_(h) isC(R₅₉R₆₀), and j is 4 to 31, wherein the first, third, fourth, sixth,seventh, ninth, tenth, twelfth, thirteenth, fifteenth, sixteenth,eighteenth, nineteenth, twenty-first, twenty-second, twenty-fourth,twenty-fifth, twenty-seventh, twenty-eighth, thirtieth, and thirty-firstR_(g), if present, are C(R₄₂R₄₃) and the second, fifth, eighth,eleventh, fourteenth, seventeenth, twentieth, twenty-third,twenty-sixth, and twenty-ninth, R_(g), if present, are O, wherein R₅₉,R₆₀, R₄₂, and R₄₃ are hydrogen or C₁-C₃ alkyl. In some embodiments R₅₉and R₆₀ are hydrogen. In some embodiments R₅₉ is hydrogen and R₆₀ isC₁-C₃ alkyl. In some embodiments R₅₉ and Reo are C₁-C₃ alkyl. In someembodiments all R₄₃ are hydrogen. In some embodiments all but one R₄₂are hydrogen. In some embodiments all but two R₄₂ are hydrogen. In someembodiments all but three R₄₂ are hydrogen. In some embodiments all butfour R₄₂ are hydrogen. In some embodiments all but five R₄₂ arehydrogen. In some embodiments all but six R₄₂ are hydrogen. In someembodiments all but seven R₄₂ are hydrogen. In some embodiments all buteight R₄₂ are hydrogen. In some embodiments all but nine R₄₂ arehydrogen. In some embodiments all but ten R₄₂ are hydrogen. In someembodiments all but eleven R₄₂ are hydrogen. In some embodiments all buttwelve R₄₂ are hydrogen. In some embodiments all R₄₃ are hydrogen. Insome embodiments all but one R₄₃ are hydrogen. In some embodiments allbut two R₄₂ are hydrogen. In some embodiments all but three R₄₂ arehydrogen. In some embodiments all but four R₄₃ are hydrogen. In someembodiments all but five R₄₃ are hydrogen. In some embodiments all butsix R₄₃ are hydrogen. In some embodiments all but seven R₄₂ arehydrogen. In some embodiments all but eight R₄₃ are hydrogen. In someembodiments all but nine R₄₃ are hydrogen. In some embodiments all butten R₄₂ are hydrogen. In some embodiments all but eleven R₄₂ arehydrogen. In some embodiments all but twelve R₄₃ are hydrogen.

In some embodiments where A or R₆ is —R_(h)—(R_(g))_(j), R_(h) isC(R₅₉R₆₀), and j is 10, wherein the first, third, fourth, sixth,seventh, ninth, and tenth R_(g) are C(R₄₂R₄₃) and the second, fifth, andeighth R_(g) are O, and wherein R₅₉, R₆₀, R₄₂, and R₄₃ are hydrogen.

In some embodiments, in Formula IX, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ arecarbon, y is 1, R^(e) is —O—CH₃, the ring of Formula IX is aromatic, R₂₄is —(CR₂₅R₂₅)_(p)—, and p is 0. In some embodiments, R^(e) is at R₂₁. Insome embodiments, R^(e) is at R₁₉. In some embodiments, R^(e) is at R₂₀.In some embodiments, R^(e) is at R₂₂. In some embodiments, R^(e) is atR₂₃.

Z2-Y13

In some embodiments, the compounds are represented by the generalformula:

—X—R₁

wherein X is oxygen, sulfur, or NR₄;

wherein R₁ is -A-B(—C)_(δ) or —R₆—R^(b);

wherein A and R₆ are

wherein for A and R₆, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are carbon, y is1, R^(e) is R^(b), the ring of Formula IX is aromatic, R₂₄ is—(CR₂₅R₂₅)_(p)—, p is 0 to 10, and R₂₅ are independently hydrogen orC₁-C₃ alkyl;

wherein B and R^(b)

wherein each C, R₈, and R₀ are independently hydrogen or

wherein for C, R₈, and R₉, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are carbon,y is 0, the ring of Formula IX is aromatic, R₂₄ is —(CR₂₅R₂₅)_(p)—, oneR₂₅ is —OH, the other R₂₅ is hydrogen, and p is 1;

wherein R₈ and R₉ are not both hydrogen, wherein at least one of C isnot hydrogen.

In some embodiments where A or R₆ is Formula IX, R^(e) is at R₂₁. Insome embodiments, R^(e) is at R₁₉. In some embodiments, R^(e) is at R₂₀.In some embodiments, R^(e) is at R₂₂. In some embodiments, R^(e) is atR₂₃. In some embodiments, p is 0. In some embodiments p is 1. In someembodiment p is 2. In some embodiments p is 3. In some embodiment p is4. In some embodiments p is 5. In some embodiments p is 7. In someembodiment p is 8. In some embodiments p is 9. In some embodiments p is10. In some embodiments all R₂₅ are hydrogen. In some embodiments allbut one R₂₅ are hydrogen. In some embodiments all but two R₂₅ arehydrogen. In some embodiments all but three R₂₅ are hydrogen. In someembodiments all but four R₂₅ are hydrogen.

In some embodiments where A or R₆ is Formula IX, in such A and R₆, R₁₈,R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are carbon, y is 1, R^(e) is R^(b), the ringof Formula IX is aromatic, R₂₄ is —(CR₂₅R₂₅)_(p)—, p is 1, and R₂₅ arehydrogen.

In some embodiments, in Formula IX, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ arecarbon, y is 0, the ring of Formula IX is aromatic, R₂₄ is—(CR₂₅R₂₅)_(p)—, one R₂₅ is —OH, the other R₂₅ is hydrogen, and p is 1.

Z2-Y5

In some embodiments, the compounds are represented by the generalformula:

—X—R₁

wherein X is oxygen, sulfur, or NR₄;

wherein R₄ is -A-B(—C)_(δ) or —R₆—R^(b);

wherein A and, R₆ are

wherein for A and R₆, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are carbon, y is1, R^(e) is R^(b), the ring of Formula IX is aromatic, R₂₄ is—(CR₂₅R₂₅)_(p)—, p is 0 to 10, and R₂₅ are independently hydrogen orC₁-C₃ alkyl;

wherein B and R^(b) are:

wherein each C, R₈, and R₉ are independently hydrogen or

wherein for C, R₈, and R₉, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are carbon,y is 1, R^(e) is methyl, the ring of Formula IX is aromatic, R₂₄ is—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, p is 0, q is 0, and X_(b) is S(O)₂;

wherein R₈ and R₀ are not both hydrogen, wherein at least one of C isnot hydrogen.

In some embodiments where A or R₆ is Formula IX, R^(e) is at R₂₁. Insome embodiments, R^(e) is at R₁₉. In some embodiments, R^(e) is at R₂₀.In some embodiments, R^(e) is at R₂₂. In some embodiments, R^(e) is atR₂₃. In some embodiments, p is 0. In some embodiments p is 1. In someembodiment p is 2. In some embodiments p is 3. In some embodiment p is4. In some embodiments p is 5. In some embodiments p is 7. In someembodiment p is 8. In some embodiments p is 9. In some embodiments p is10. In some embodiments all R₂₅ are hydrogen. In some embodiments allbut one R₂₅ are hydrogen. In some embodiments all but two R₂₅ arehydrogen. In some embodiments all but three R₂₅ are hydrogen. In someembodiments all but four R₂₅ are hydrogen.

In some embodiments where A or R₆ is Formula IX, in such A and R₆, R₁₈,R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are carbon, y is 1, R^(e) is R^(b), the ringof Formula IX is aromatic, R₂₄ is —(CR₂₅R₂₅)_(p)—, p is 1, and R₂₅ arehydrogen.

In some embodiments, in Formula IX, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ arecarbon, y is 1, R^(e) is methyl, the ring of Formula IX is aromatic, R₂₄is —(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, p is 0, q is 0, and X_(b) isS(O)₂.

Z2-Y7

In some embodiments, the compounds are represented by the generalformula:

—X—R₁

wherein X is oxygen, sulfur, or NR₄;

wherein R₄ is -A-B(—C)_(δ) or —R₆—R^(b);

wherein A and R₆ are

wherein for A and R₆, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are carbon, y is1, R^(e) is R^(b), the ring of Formula IX is aromatic, R₂₄ is—(CR₂₅R₂₅)_(p)—, p is 0 to 10, and R₂₅ are independently hydrogen orC₁-C₃ alkyl;

wherein B and R^(b) are:

wherein each C, R₈, and R₀ are independently hydrogen or—R_(h)—(R_(g))_(j),

wherein R_(h) is C(R₅₉R₆₀), j is 1 to 10, one R_(g) is O, the otherR_(g) are C(R₄₂R₄₃), and R_(f) is C(R₄₅R₄₆R₄₇), wherein R₅₉, R₆₀, R₄₂,R₄₃, R₄₅, R₄₆, and R₄₃ are hydrogen;

wherein R₈ and R₉ are not both hydrogen, wherein at least one of C isnot hydrogen.

In some embodiments where A or R₆ is Formula IX, R^(e) is at R₂₁. Insome embodiments, R^(e) is at R₁₉. In some embodiments, R^(e) is at R₂₀.In some embodiments, R^(e) is at R₂₂. In some embodiments, R^(e) is atR₂₃. In some embodiments, p is 0. In some embodiments p is 1. In someembodiment p is 2. In some embodiments p is 3. In some embodiment p is4. In some embodiments p is 5. In some embodiments p is 7. In someembodiment p is 8. In some embodiments p is 9. In some embodiments p is10. In some embodiments all R₂₅ are hydrogen. In some embodiments allbut one R₂₅ are hydrogen. In some embodiments all but two R₂₅ arehydrogen. In some embodiments all but three R₂₅ are hydrogen. In someembodiments all but four R₂₅ are hydrogen.

In some embodiments where A or R₆ is Formula IX, in such A and R₆, R₁₈,R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are carbon, y is 1, R^(e) is R^(b), the ringof Formula IX is aromatic, R₂₄ is —(CR₂₅R₂₅)_(p)—, p is 1, and R₂₅ arehydrogen.

In some embodiments R_(h) is C(R₅₉R₆₀), j is 1, R_(g) is O, and R_(f) isC(R₄₅R₄₆R₄₇), wherein R₅₉, R₆₀, R₄₅, R₄₆, and R₄₇ are hydrogen. In someembodiments R_(h) is absent, j is 1, R_(g) is O, and R_(f) isC(R₄₅R₄₆R₄₇), wherein R₄₅, R₄₆, and R₄₇ are hydrogen.

In some embodiments R_(h) is C(R₅₉R₆₀), j is 1 to 10, one R_(g) is O,the other R_(g) are C(R₄₂R₄₃), and R_(f) is C(R₄₅R₄₆R₄₇), wherein R₅₉,R₆₀, R₄₂, R₄₃, R₄₅, R₄₆, and R₄₇ are hydrogen. In some embodiments thelast R_(g) is O. In some embodiments the penultimate R_(g) is O. In someembodiments the antepenultimate R_(g) is O. In some embodiments thefourth from the last R_(g) is O. In some embodiments the fifth from thelast R_(g) is O. In some embodiments the first R_(g) is O. In someembodiments the second R_(g) is O. In some embodiments the third R_(g)is O. In some embodiments the fourth R_(g) is O. In some embodiments thefifth R_(g) is O.

Z2-Y6

In some embodiments, the compounds are represented by the generalformula:

—X—R₁

wherein X is oxygen, sulfur, or NR₄;

wherein R₄ is -A-B(—C)_(δ) or —R₆—R^(b);

wherein A and R₆ are

wherein for A and R₆, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are carbon, y is1, R^(e) is R^(b), the ring of Formula IX is aromatic, R₂₄ is—(CR₂₅R₂₅)_(p)—, p is 0 to 10, and R₂₅ are independently hydrogen orC₁-C₃ alkyl;

wherein B and R^(b) are:

wherein each C, R₈, and R₉ are independently hydrogen or—R_(h)—(R_(g))_(j),

wherein for C and R₉, R_(h) is NR₆₁, j is 0 to 10, and each R_(g) isC(R₄₂R₄₃), wherein R₆₁ is —R_(hx)—(R_(gx))_(jx)—R_(fx), and R₄₂ and R₄₃are hydrogen, wherein R_(hx) is C(R_(59x)R_(60x)), jx=0 to 10, R_(gx) isC(R_(42x)R_(43x)), and R_(fx) is C(R_(45x)R_(46x)R_(47x)), and whereinR_(59x), R_(60x), R_(42x), R_(43x), R_(45x), R_(46x), R_(47x) arehydrogen; wherein for C and R₈, R_(h) is C(R₅₉R₆₀), j is 0 to 10, andeach R_(g) is C(R₄₂R₄₃), wherein R₅₉, R₆₀R₄₂, R₄₃ are hydrogen;

wherein R₈ and R₉ are not both hydrogen, wherein at least one of C isnot hydrogen.

In some embodiments where A or R₆ is Formula IX, R^(e) is at R₂₁. Insome embodiments, R^(e) is at R₁₉. In some embodiments, R^(e) is at R₂₀.In some embodiments, R^(e) is at R₂₂. In some embodiments, R^(e) is atR₂₃. In some embodiments, p is 0. In some embodiments p is 1. In someembodiment p is 2. In some embodiments p is 3. In some embodiment p is4. In some embodiments p is 5. In some embodiments p is 7. In someembodiment p is 8. In some embodiments p is 9. In some embodiments p is10. In some embodiments all R₂₅ are hydrogen. In some embodiments allbut one R₂₅ are hydrogen. In some embodiments all but two R₂₅ arehydrogen. In some embodiments all but three R₂₅ are hydrogen. In someembodiments all but four R₂₅ are hydrogen.

In some embodiments where A or R₆ is Formula IX, in such A and R₆, R₁₈,R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are carbon, y is 1, R^(e) is R^(b), the ringof Formula IX is aromatic, R₂₄ is —(CR₂₅R₂₅)_(p)—, p is 1, and R₂₅ arehydrogen.

In some embodiments R_(h) is NR₆₁, j is 1, and R_(g) is C(R₄₂R₄₃),wherein R₆₁ is —R_(hx)—(R_(gx))_(jx)—R_(fx), and R₄₂ and R₄₃ arehydrogen, wherein R_(hx) is absent, jx=1, R_(gx) is C(R_(42x)R_(43x)),and R_(fx) is C(R_(45x)R_(46x)R_(47x)), and wherein R_(42x), R_(43x),R_(45x), R_(46x), R_(47x) are hydrogen.

In some embodiments R_(h) is NR₆₁, j is 0 to 10, and each R_(g) isC(R₄₂R₄₃), wherein R₆₁ is —R_(hx)—(R_(gx))_(jx)—R_(fx), and R₄₂ and R₄₃are hydrogen, wherein R_(hx) is C(R_(59x)R_(60x)), jx=0 to 10, R_(gx) isC(R_(42x)R_(43x)), and R_(fx) is C(R_(45x)R_(46x)R_(47x)), and whereinR_(59x), R_(60x), R_(42x), R_(43x), R_(45x), R_(46x), R_(47x) arehydrogen. In some embodiments j=jx. In some embodiments j and jx are 0.In some embodiment j and jx are 2. In some embodiments j and jx are 3.In some embodiments j and jx are 4.

In some embodiments R_(h) is C(R₅₉R₆₀), and j is 0, wherein R₅₉ and R₆₀are hydrogen. In some embodiments R_(h) is C(R₅₉R₆₀), j is 0 to 10, andeach R_(g) is C(R₄₂R₄₃), wherein R₅₉, R₆₀ R₄₂, R₄₃ are hydrogen. In someembodiments j is 1. In some embodiment j is 2. In some embodiments j is3. In some embodiments j is 4.

Z1-Y10

In some embodiments, compounds are represented by the general formula:

—X—R₁

wherein X is oxygen, sulfur, or NR₄;

wherein R₁ is -A-B(—C)_(δ) or —R₆—R^(b);

wherein A and R₆ are —R_(h)—(R_(g))_(j),

wherein R_(h) is C(R₅₉R₆₀), and j is 4 to 31, wherein the first, third,fourth, sixth, seventh, ninth, tenth, twelfth, thirteenth, fifteenth,sixteenth, eighteenth, nineteenth, twenty-first, twenty-second,twenty-fourth, twenty-fifth, twenty-seventh, twenty-eighth, thirtieth,and thirty-first R_(g), if present, are C(R₄₂R₄₃) and the second, fifth,eighth, eleventh, fourteenth, seventeenth, twentieth, twenty-third,twenty-sixth, and twenty-ninth, R_(g), if present, are O, wherein R₅₉,R₆₀, R₄₂, and R₄₃ are independently hydrogen or C₁-C₃ alkyl;

wherein B and R^(b) are:

wherein each C, R₈, and R₀ are independently hydrogen or—R_(h)—(R_(g))_(j),

wherein R_(h) is absent, j is 1 to 10, and each R_(g) is C(R₄₂R₄₃),wherein R₄₂ and R₄₃ are hydrogen;

wherein R₈ and R₀ are not both hydrogen, wherein at least one of C isnot hydrogen.

In some embodiments where A or R₆ is —R_(h)—(R_(g))_(j), R_(h) isC(R₅₉R₆₀), and j is 4 to 31, wherein the first, third, fourth, sixth,seventh, ninth, tenth, twelfth, thirteenth, fifteenth, sixteenth,eighteenth, nineteenth, twenty-first, twenty-second, twenty-fourth,twenty-fifth, twenty-seventh, twenty-eighth, thirtieth, and thirty-firstR_(g), if present, are C(R₄₂R₄₃) and the second, fifth, eighth,eleventh, fourteenth, seventeenth, twentieth, twenty-third,twenty-sixth, and twenty-ninth, R_(g), if present, are O, wherein R₅₉,R₆₀, R₄₂, and RB are hydrogen or C₁-C₃ alkyl. In some embodiments R₅₉and R₆₀ are hydrogen. In some embodiments R₅₉ is hydrogen and R₆₀ isC₁-C₃ alkyl. In some embodiments R₅₉ and R₆₀ are C₁-C₃ alkyl. In someembodiments all RB are hydrogen. In some embodiments all but one R₄₂ arehydrogen. In some embodiments all but two R₄₂ are hydrogen. In someembodiments all but three R₄₃ are hydrogen. In some embodiments all butfour R₄₂ are hydrogen. In some embodiments all but five R₄₃ arehydrogen. In some embodiments all but six R₄₃ are hydrogen. In someembodiments all but seven R₄₂ are hydrogen. In some embodiments all buteight R₄₃ are hydrogen. In some embodiments all but nine R₄₃ arehydrogen. In some embodiments all but ten R₄₂ are hydrogen. In someembodiments all but eleven R₄₃ are hydrogen. In some embodiments all buttwelve R₄₂ are hydrogen. In some embodiments all R₄₃ are hydrogen. Insome embodiments all but one R₄₃ are hydrogen. In some embodiments allbut two R₄₃ are hydrogen. In some embodiments all but three R₄₃ arehydrogen. In some embodiments all but four R₄₃ are hydrogen. In someembodiments all but five R₄₃ are hydrogen. In some embodiments all butsix R₄₃ are hydrogen. In some embodiments all but seven R₄₃ arehydrogen. In some embodiments all but eight R₄₃ are hydrogen. In someembodiments all but nine R₄₃ are hydrogen. In some embodiments all butten R₄₃ are hydrogen. In some embodiments all but eleven R₄₃ arehydrogen. In some embodiments all but twelve R₄₃ are hydrogen.

In some embodiments where A or R₆ is —R_(h)—(R_(g))_(j), R_(h) isC(R₅₉R₆₀), and j is 10, wherein the first, third, fourth, sixth,seventh, ninth, and tenth R_(g) are C(R₄₂R₄₃) and the second, fifth, andeighth R_(g) are O, and wherein R₅₉, R₆₀, R₄₂, and R₄₃ are hydrogen.

In some embodiments R_(h) is absent, j is 6, and each R_(g) isC(R₄₂R₄₃), wherein R₄₂ and R₄₃ are hydrogen. In some embodiments R_(h)is absent, j is 1 to 10, and each R_(g) is C(R₄₂R₄₃), wherein R₄₂ andR₄₃ are hydrogen. In some embodiments j is 3. In some embodiment j is 4.In some embodiments j is 5. In some embodiments j is 7. In someembodiment j is 8. In some embodiments j is 9. In some embodiments j is10.

Z1-Y11

In some embodiments, compounds are represented by the general formula:

—X—R₁

wherein X is oxygen, sulfur, or NR₄;

wherein R₄ is -A-B(—C)_(δ) or —R₆—R^(b);

wherein A and R₅ are —R_(h)—(R_(g))_(j),

wherein R_(h) is C(R₅₉R₅₀), and j is 4 to 31, wherein the first, third,fourth, sixth, seventh, ninth, tenth, twelfth, thirteenth, fifteenth,sixteenth, eighteenth, nineteenth, twenty-first, twenty-second,twenty-fourth, twenty-fifth, twenty-seventh, twenty-eighth, thirtieth,and thirty-first R_(g), if present, are C(R₄₂R₄₃) and the second, fifth,eighth, eleventh, fourteenth, seventeenth, twentieth, twenty-third,twenty-sixth, and twenty-ninth, R_(g), if present, are O, wherein R₅₉,R₆₀, R₄₂, and R₄₃ are independently hydrogen or C₁-C₃ alkyl;

wherein B and R^(b) are;

wherein each C, R₈, and R₀ are independently hydrogen or—R_(h)—(R_(g))_(j),

wherein R_(h) is C(R₅₉R₆₀), j is 1 to 10, one R_(g) is O, and the otherR_(g) are C(R₄₂R₄₃), wherein R₅₉, R₆₀, R₄₂, and R₄₃ are hydrogen;

wherein R₈ and R₉ are not both hydrogen, wherein at least one of C isnot hydrogen.

In some embodiments where A or R₆ is —R_(h)—(R_(g))_(j), R_(h) isC(R₅₉R₆₀), and j is 4 to 31, wherein the first, third, fourth, sixth,seventh, ninth, tenth, twelfth, thirteenth, fifteenth, sixteenth,eighteenth, nineteenth, twenty-first, twenty-second, twenty-fourth,twenty-fifth, twenty-seventh, twenty-eighth, thirtieth, and thirty-firstR_(g), if present, are C(R₄₂R₄₃) and the second, fifth, eighth,eleventh, fourteenth, seventeenth, twentieth, twenty-third,twenty-sixth, and twenty-ninth, R_(g), if present, are O, wherein R₅₉,R₆₀, R₄₂, and RB are hydrogen or C₁-C₃ alkyl. In some embodiments R₅₉and R₆₀ are hydrogen. In some embodiments R₅₉ is hydrogen and R₆₀ isC₁-C₃ alkyl. In some embodiments R₅₉ and R₆₀ are C₁-C₃ alkyl. In someembodiments all RB are hydrogen. In some embodiments all but one RB arehydrogen. In some embodiments all but two RB are hydrogen. In someembodiments all but three RB are hydrogen. In some embodiments all butfour R₄₂ are hydrogen. In some embodiments all but five RB are hydrogen.In some embodiments all but six RB are hydrogen. In some embodiments allbut seven R₄₂ are hydrogen. In some embodiments all but eight RB arehydrogen. In some embodiments all but nine RB are hydrogen. In someembodiments all but ten R₄₂ are hydrogen. In some embodiments all buteleven R₄₂ are hydrogen. In some embodiments all but twelve R₄₂ arehydrogen. In some embodiments all R₄₃ are hydrogen. In some embodimentsall but one RB are hydrogen. In some embodiments all but two RB arehydrogen. In some embodiments all but three RB are hydrogen. In someembodiments all but four R₄₃ are hydrogen. In some embodiments all butfive R₄₃ are hydrogen. In some embodiments all but six R₄₃ are hydrogen.In some embodiments all but seven R₄₃ are hydrogen. In some embodimentsall but eight R₄₃ are hydrogen. In some embodiments all but nine R₄₃ arehydrogen. In some embodiments all but ten R₄₃ are hydrogen. In someembodiments all but eleven R₄₃ are hydrogen. In some embodiments all buttwelve R₄₃ are hydrogen.

In some embodiments where A or R₆ is —R_(h)—(R_(g))_(j), R_(h) isC(R₅₉R₆₀), and j is 10, wherein the first, third, fourth, sixth,seventh, ninth, and tenth R_(g) are C(R₄₂R₄₃) and the second, fifth, andeighth R_(g) are O, and wherein R₅₉, R₆₀, R₄₂, and R₄₃ are hydrogen.

In some embodiments R_(h) is C(R₅₉R₆₀), j is 3, the first R_(g) is O,and the second and third R_(g) are C(R₄₂R₄₃), wherein R₅₉, R₆₀, R₄₂, andR₄₃ are hydrogen. In some embodiments R_(h) is C(R₅₉R₆₀), j is 1 to 10,one R_(g) is O, and the other R_(g) are C(R₄₂R₄₃), wherein R₅₉, R₅₀,R₄₂, and R₄₃ are hydrogen. In some embodiments the first R_(g) is O. Insome embodiments the second R_(g) is O. In some embodiments the thirdR_(g) is O. In some embodiments the fourth R_(g) is O. In someembodiments the fifth R_(g) is O. In some embodiments the fifth from thelast R_(g) is O. In some embodiments the fourth from the last R_(g) isO. In some embodiments the antepenultimate R_(g) is O. In someembodiments the penultimate R_(g) is O. In some embodiments the lastR_(g) is O.

In some embodiments R_(h) is C(R₅₉R₆₀), j is 4 to 16, two R_(g) are O,and the other R_(g) are C(R₄₂R₄₃), wherein R₅₉, R₅₀, R₄₂, and R₄₃ arehydrogen. In some embodiments the first and third R_(g) are O. In someembodiments the first and fourth R_(g) are O. In some embodiments thefirst and fifth R_(g) are O. In some embodiments the first and sixthR_(g) are O. In some embodiments the first and seventh R_(g) are O. Insome embodiments the first and eighth R_(g) are O. In some embodimentsthe first and ninth R_(g) are O. In some embodiments the first and tenthR_(g) are O. In some embodiments the first and eleventh R_(g) are O. Insome embodiments the first and twelfth R_(g) are O. In some embodimentsthe first and thirteenth R_(g) are O. In some embodiments the first andfourteenth R_(g) are O. In some embodiments the first and fifteenthR_(g) are O. In some embodiments the second and fourth R_(g) are O. Insome embodiments the second and fifth R_(g) are O. In some embodimentsthe second and sixth R_(g) are O. In some embodiments the second andseventh R_(g) are O. In some embodiments the second and eighth R_(g) areO. In some embodiments the second and ninth R_(g) are O. In someembodiments the second and tenth R_(g) are O. In some embodiments thesecond and eleventh R_(g) are O. In some embodiments the second andtwelfth R_(g) are O. In some embodiments the second and thirteenth R_(g)are O. In some embodiments the second and fourteenth R_(g) are O. Insome embodiments the second and fifteenth R_(g) are O. In someembodiments the third and fifth R_(g) are O. In some embodiments thethird and sixth R_(g) are O. In some embodiments the third and seventhR_(g) are O. In some embodiments the third and eighth R_(g) are O. Insome embodiments the third and ninth R_(g) are O. In some embodimentsthe third and tenth R_(g) are O. In some embodiments the third andeleventh R_(g) are O. In some embodiments the third and twelfth R_(g)are O. In some embodiments the third and thirteenth R_(g) are O. In someembodiments the third and fourteenth R_(g) are O. In some embodimentsthe third and fifteenth R_(g) are O. In some embodiments the fourth andsixth R_(g) are O. In some embodiments the fourth and seventh R_(g) areO. In some embodiments the fourth and eighth R_(g) are O. In someembodiments the fourth and ninth R_(g) are O. In some embodiments thefourth and tenth R_(g) are O. In some embodiments the fourth andeleventh R_(g) are O. In some embodiments the fourth and twelfth R_(g)are O. In some embodiments the fourth and thirteenth R_(g) are O. Insome embodiments the fourth and fourteenth R_(g) are O. In someembodiments the fourth and fifteenth R_(g) are O. In some embodimentsthe fifth and seventh R_(g) are O. In some embodiments the fifth andeighth R_(g) are O. In some embodiments the fifth and ninth R_(g) are O.In some embodiments the fifth and tenth R_(g) are O. In some embodimentsthe fifth and eleventh R_(g) are O. In some embodiments the fifth andtwelfth R_(g) are O. In some embodiments the fifth and thirteenth R_(g)are O. In some embodiments the fifth and fourteenth R_(g) are O. In someembodiments the fifth and fifteenth R_(g) are O. In some embodiments thesixth and eighth R_(g) are O. In some embodiments the sixth and ninthR_(g) are O. In some embodiments the sixth and tenth R_(g) are O. Insome embodiments the sixth and eleventh R_(g) are O. In some embodimentsthe sixth and twelfth R_(g) are O. In some embodiments the sixth andthirteenth R_(g) are O. In some embodiments the sixth and fourteenthR_(g) are O. In some embodiments the sixth and fifteenth R_(g) are O. Insome embodiments the seventh and ninth R_(g) are O. In some embodimentsthe seventh and tenth R_(g) are O. In some embodiments the seventh andeleventh R_(g) are O. In some embodiments the seventh and twelfth R_(g)are O. In some embodiments the seventh and thirteenth R_(g) are O. Insome embodiments the seventh and fourteenth R_(g) are O. In someembodiments the seventh and fifteenth R_(g) are O. In some embodimentsthe eighth and tenth R_(g) are O. In some embodiments the eighth andeleventh R_(g) are O. In some embodiments the eighth and twelfth R_(g)are O. In some embodiments the eighth and thirteenth R_(g) are O. Insome embodiments the eighth and fourteenth R_(g) are O. In someembodiments the eighth and fifteenth R_(g) are O. In some embodimentsthe ninth and eleventh R_(g) are O. In some embodiments the ninth andtwelfth R_(g) are O. In some embodiments the ninth and thirteenth R_(g)are O. In some embodiments the ninth and fourteenth R_(g) are O. In someembodiments the ninth and fifteenth R_(g) are O. In some embodiments thetenth and twelfth R_(g) are O. In some embodiments the tenth andthirteenth R_(g) are O. In some embodiments the tenth and fourteenthR_(g) are O. In some embodiments the tenth and fifteenth R_(g) are O. Insome embodiments the eleventh and thirteenth R_(g) are O. In someembodiments the eleventh and fourteenth R_(g) are O. In some embodimentsthe eleventh and fifteenth R_(g) are O. In some embodiments the twelfthand fourteenth R_(g) are O. In some embodiments the twelfth andfifteenth R_(g) are O. In some embodiments the thirteenth and fifteenthR_(g) are O.

Z1-Y2

In some embodiments, compounds are represented by the general formula:

—X—R₁

wherein X is oxygen, sulfur, or NR₄;

wherein R₄ is -A-B(—C)_(δ) or —R₆—R^(b);

wherein A and R₆ are —R_(h)—(R_(g))_(j),

wherein R_(h) is C(R₅₉R₆₀), and j is 4 to 31, wherein the first, third,fourth, sixth, seventh, ninth, tenth, twelfth, thirteenth, fifteenth,sixteenth, eighteenth, nineteenth, twenty-first, twenty-second,twenty-fourth, twenty-fifth, twenty-seventh, twenty-eighth, thirtieth,and thirty-first R_(g), if present, are C(R₄₂R₄₃) and the second, fifth,eighth, eleventh, fourteenth, seventeenth, twentieth, twenty-third,twenty-sixth, and twenty-ninth, R_(g), if present, are O, wherein R₅₉,R₆₀, R₄₂, and R₄₃ are independently hydrogen or C₁-C₃ alkyl;

wherein B and R^(b) are:

wherein each C, R₈, and R₀ are independently hydrogen or

wherein for C, R₈, and R₀, R₁₉ and R₂₀ are oxygen, R₁₈, R₂₁, and R₂₂ arecarbon, w is 0, the ring of Formula XIV has no double bonds, R₂₄ is—(CR₂₅R₂₅)_(p)—, both R₂₅ are hydrogen, and p is 1;

wherein R₈ and R₀ are not both hydrogen, wherein at least one of C isnot hydrogen.

In some embodiments where A or R₆ is —R_(h)—(R_(g))_(j), R_(h) isC(R₅₉R₆₀), and j is 4 to 31, wherein the first, third, fourth, sixth,seventh, ninth, tenth, twelfth, thirteenth, fifteenth, sixteenth,eighteenth, nineteenth, twenty-first, twenty-second, twenty-fourth,twenty-fifth, twenty-seventh, twenty-eighth, thirtieth, and thirty-firstR_(g), if present, are C(R₄₂R₄₃) and the second, fifth, eighth,eleventh, fourteenth, seventeenth, twentieth, twenty-third,twenty-sixth, and twenty-ninth, R_(g), if present, are O, wherein R₅₉,R₆₀, R₄₂, and R₄₃ are hydrogen or C₁-C₃ alkyl. In some embodiments R₅₉and R₆₀ are hydrogen. In some embodiments R₅₉ is hydrogen and R₆₀ isC₁-C₃ alkyl. In some embodiments R₅₉ and R₆₀ are C₁-C₃ alkyl. In someembodiments all R₄₂ are hydrogen. In some embodiments all but one R₄₃are hydrogen. In some embodiments all but two R₄₃ are hydrogen. In someembodiments all but three R₄₃ are hydrogen. In some embodiments all butfour R₄₂ are hydrogen. In some embodiments all but five R₄₃ arehydrogen. In some embodiments all but six R₄₃ are hydrogen. In someembodiments all but seven R₄₂ are hydrogen. In some embodiments all buteight R₄₃ are hydrogen. In some embodiments all but nine R₄₃ arehydrogen. In some embodiments all but ten R₄₂ are hydrogen. In someembodiments all but eleven R₄₃ are hydrogen. In some embodiments all buttwelve R₄₂ are hydrogen. In some embodiments all R₄₃ are hydrogen. Insome embodiments all but one R₄₃ are hydrogen. In some embodiments allbut two R₄₃ are hydrogen. In some embodiments all but three R₄₃ arehydrogen. In some embodiments all but four R₄₃ are hydrogen. In someembodiments all but five R₄₃ are hydrogen. In some embodiments all butsix R₄₃ are hydrogen. In some embodiments all but seven R₄₃ arehydrogen. In some embodiments all but eight R₄₃ are hydrogen. In someembodiments all but nine R₄₃ are hydrogen. In some embodiments all butten R₄₃ are hydrogen. In some embodiments all but eleven R₄₃ arehydrogen. In some embodiments all but twelve R₄₃ are hydrogen.

In some embodiments where A or R₆ is —R_(h)—(R_(g))_(j), R_(h) isC(R₅₉R₆₀), and j is 10, wherein the first, third, fourth, sixth,seventh, ninth, and tenth R_(g) are C(R₄₂R₄₃) and the second, fifth, andeighth R_(g) are O, and wherein R₅₉, R₆₀, R₄₂, and R₄₃ are hydrogen.

In some embodiments, in Formula XIV, R₁₉ and R₂₀ are oxygen, R₁₈, R₂₁,and R₂₂ are carbon, w is 0, the ring of Formula XIV has no double bonds,R₂₄ is —(CR₂₅R₂₅)_(p)—, both R₂₅ are hydrogen, and p is 1.

Modified alginate polymers can be of any desired molecular weight. Theweight average molecular weight of the alginates is preferably between1,000 and 1,000,000 Daltons, more preferably between 10,000 and 500,000Daltons as determined by gel permeation chromatography.

Modified alginate polymers can contain any ratio of mannuronatemonomers, guluronate monomers, and covalently modified monomers. In someembodiments, greater than 2.5%, 5%, 7.5%, 10%, 12%, 14%, 15%, 16%, 18%,20%, 22%, 24%, 25%, 26%, 28%, 30%, 32.5%, 35%, 37.5%, 40%, 45%, 50%,55%, or 60% of the monomers in the modified alginate polymer arecovalently modified monomers. Preferably greater than 10%, morepreferably greater than 20%, and most preferably greater than 30% of themonomers in the modified alginate polymer are covalently modifiedmonomers.

Modified alginate polymers can be produced incorporating covalentlymodified monomers possessing a range of different hydrogen bondingpotentials, hydrophobicities/hydrophilicities, and charge states. Theinclusion of covalently modified monomers into an alginate polymeralters the physiochemical properties of alginate polymer. Accordingly,the physiochemical properties of alginates can be tuned for desiredapplications by the selective incorporation of covalently modifiedmonomers.

For example, the glass transition temperature (T_(g)), can be varied bythe incorporation of covalently modified monomers. In some embodiments,the modified alginate polymer powder possess a T_(g), as measured bydifferential scanning calorimetry (DSC), of greater than 50° C., 60° C.,65° C., 70° C., 75° C., 80° C., 85° C., 90° C., 95° C., 100° C., 105°C., 110° C., 115° C., 120° C., 125° C., 130° C., 135° C., 140° C., 145°C., 150° C., 160° C., 175° C., 190° C., or 200° C.

The hydrophobicity/hydrophilicity of alginates can be varied by theincorporation of hydrophobic and/or hydrophilic covalently modifiedmonomers. In preferred embodiments, the modified alginate polymercontains one or more hydrophobic covalently modified monomers. Therelative hydrophobicity/hydrophilicity of modified alginates can bequantitatively assessed by measuring the contact angle of a waterdroplet on a film of the modified alginate polymer using a goniometer.In some embodiments, the modified alginate has a contact angle of lessthan 90° (i.e. it is hydrophilic). In preferred embodiments, themodified alginate has a contact angle of more than 90° (i.e. it ishydrophobic). In some embodiments, the modified alginate has a contactangle of more than 95°, 100°, 105°, 110°, 115°, or 120°.

In embodiments used for cell encapsulation, the modified alginatepolymer can be ionically crosslinked by a polyvalent cation such asCa²⁺, Sr²⁺, or Ba²⁺ to form hydrogels. The ability of modified alginatesto form stable hydrogels in physiological conditions can be quantifiedusing the hydrogel formation assay described in Example 2.

In some embodiments, the modified alginate polymer forms hydrogels suchthat the fluorescence intensity measured using the high throughputhydrogel formation assay described herein is greater than 10,000,15,000, 20,000, 25,000, 30,000, 35,000, 40,000, 45,000, 50,000, or55,000. In preferred embodiments, the modified alginate polymer formshydrogels such that the fluorescence intensity measured using the highthroughput hydrogel formation assay described herein is greater than15,000. In preferred embodiments, the modified alginate polymer formshydrogels such that the fluorescence intensity measured using the highthroughput hydrogel formation assay described herein is between 15,000and 55,000, preferably between 20,000 and 55,000, more preferablybetween 25,000 and 55,000.

In embodiments used for cell encapsulation, the modified alginatepolymer forms a hydrogel with sufficient porosity to permit nutrients,waste, and the hormones and/or proteins secreted from encapsulated cellsto diffuse freely into and out of the capsules, while simultaneouslypreventing the incursion of immune cells into the gel matrix. Theporosity and surface area of modified alginate hydrogels can be measuredusing BET analysis. Prior to BET analysis, solvent and volatileimpurities are removed by prolonged heating of the modified alginate gelunder vacuum. Subsequently, the hydrogel samples are cooled undervacuum, for example by liquid nitrogen, and analyzed by measuring thevolume of gas (typically N₂, Kr, CO₂, or Ar gas) adsorbed to thehydrogel at specific pressures. Analysis of the physisorption of the gasat variable pressures is used to characterize the total surface area andporosity of gels formed by the modified alginate polymers. The preferredmethod of determining hydrogel porosity is BET analysis.

In preferred embodiments, the modified alginate forms a hydrogel withsufficient porosity to permit nutrients, waste, and the hormones and/orproteins secreted from encapsulated cells to diffuse freely into and outof the capsules, while simultaneously preventing the incursion of immunecells into the gel matrix. In some embodiments, the porosity of thehydrogel formed by the modified alginate polymer is increased by 5%,10%, 15%, or 20% relative to the porosity of a hydrogel formed from theunmodified alginate polymer. In alternative embodiments, the porosity ofthe hydrogel formed by the modified alginate polymer is decreased by 5%,10%, 15%, or 20% relative to the porosity of a hydrogel formed from theunmodified alginate polymer.

In preferred embodiments used for cell encapsulation, the modifiedalginate is biocompatible. The biocompatibility of modified alginatescan be quantitatively determined using the fluorescence-based in vivobiocompatibility assay described in Example 5. In this assay, cathepsinactivity was measured using an in vivo fluorescence assay to quantifythe foreign body response to the modified alginate.

In some embodiments, the modified alginate polymer is biocompatible suchthat the fluorescence response normalized to unmodified alginatemeasured using the in vivo biocompatibility assay described herein isless than 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%,or 40%. In preferred embodiments, the modified alginate polymer inducesa lower foreign body response than unmodified alginate. This isindicated by fluorescence response normalized to unmodified alginate ofless than 100%. In some embodiments, the modified alginate polymer isbiocompatible such that the fluorescence response normalized tounmodified alginate measured using the in vivo biocompatibility assaydescribed herein is less than 75%, more preferably less than 65%, andmost preferably less than 50%.

The modified alginates can be chemically modified as described herein toany desired density of modifications. The density of modifications isthe average number of modifications (that is, attached compounds) per agiven weight, volume, or area of the surface of a capsule or productthat includes the modified alginate. Generally, a density at or above athreshold density can provide a beneficial effect, such as lower foreignbody response. In some embodiments, a high density is not required.Without being bound to any particular theory of operation, it isbelieved that the chemical modifications signal to, indicate to, or areidentified by, one or more immune system or other body components toresult in a beneficial effect, such as a lower foreign body response. Insome embodiments, a lower density of modifications can be effective forthis purpose.

Useful densities include densities of at least, of less than, of about,or of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100,110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240,250, 260, 270, 280, 290, 300, 320, 340, 360, 380, 400, 420, 440, 460,480, 500, 550, 600, 650, 700, 750, 800, 850, 900, and 1000 modificationsper square μm, per μg, or per cubic μm. All ranges defined by any pairof these densities are also specifically contemplated and disclosed.

In some embodiments, the density of the modifications on a surface,surfaces, or portions of a surface(s) of a capsule or product that, whenthe product is administered to (e.g., implanted in the body of) asubject, would be in contact with fluid(s), cell(s), tissue(s), othercomponent(s), or a combination thereof of the subject's body is greaterthan the density of the modifications on other surfaces of the product.

Density can also be expressed in terms of the concentration of thesurface modifications as measured by X-ray photoelectron spectroscopy(XPS). XPS is a surface-sensitive quantitative spectroscopic techniquethat measures the elemental composition at the parts per thousand rangeof the elements that exist within a material. XPS spectra are obtainedby irradiating a material with a beam of X-rays while simultaneouslymeasuring the kinetic energy and number of electrons that escape fromthe top 0 to 10 nm of the material being analyzed. By measuring allelements present on the surface, the percentage of the elements thatcome from the surface modifications can be calculated. This can beaccomplished by, for example, taking the percentage of nitrogen (and/orother elements in the surface modifications) in the total elementalsignal measured. Nitrogen is a useful indicator for the surfacemodification because many substrated and materials forming the capsuleor product contain little nitrogen. For convenience, the percent of theelement(s) used to indicate the surface modifications can be stated asthe percent surface modifications. Also for convenience, the percentsurface modifications can be referred to as the concentration of surfacemodifications.

Useful percent surface modifications include concentrations of about0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55,60, 65, 70, 75, 80, 85, 90, 95, and 100 percent surface modifications.All ranges defined by any pair of these concentrations are alsospecifically contemplated and disclosed.

Useful percent surface modifications also include concentrations of lessthan 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45,50, 55, 60, 65, 70, 75, 80, 85, 90, 95, and 100 percent surfacemodifications. All ranges defined by any pair of these concentrationsare also specifically contemplated and disclosed.

Useful percent surface modifications also include concentrations of 0.1,0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60,65, 70, 75, 80, 85, 90, 95, and 100 percent surface modifications. Allranges defined by any pair of these concentrations are also specificallycontemplated and disclosed.

B. Capsules and Particle Morphology

Capsules are particles having a mean diameter of about 150 μm to about 5cm. The disclosed capsules can be formed of cross-linked hydrogel. Otherthan the encapsulated material, the capsules, for example, can be formedsolely of cross-linked hydrogel, can have a cross-linked hydrogel corethat is surrounded by one or more polymeric shells, can have one or morecross-linked hydrogel layers, can have a cross-linked hydrogel coating,or a combination thereof. The capsule may have any shape suitable for,for example, cell encapsulation. The capsule may contain one or morecells dispersed in the cross-linked hydrogel, thereby “encapsulating”the cells. Preferred capsules are formed of or include one or more ofthe disclosed modified alginates. Preferred capsules have a meandiameter of about 150 μm to about 8 mm.

The capsules can have any mean diameter from about 150 μm to about 5 cm.Preferably the capsules have a mean diameter that is greater than 1 mm,preferably 1.5 mm or greater. In some embodiments, the capsules can beas large as about 8 mm in diameter. For example, the capsule can be in asize range of about 1 mm to 8 mm, 1 mm to 6 mm, 1 mm to 5 mm, 1 mm to 4mm, 1 mm to 3 mm, 1 mm to 2 mm, 1 mm to 1.5 mm, 1.5 mm to 8 mm, 1.5 mmto 6 mm, 1.5 mm to 5 mm, 1.5 mm to 4 mm, 1.5 mm to 3 mm, or 1.5 mm to 2mm.

The rate of molecules entering the capsule necessary for cell viabilityand the rate of therapeutic products and waste material exiting thecapsule membrane can be selected by modulating capsule permeability.Capsule permeability can also be modified to limit entry of immunecells, antibodies, and cytokines into the capsule. Generally, as shownby the examples, known methods of forming hydrogel capsules can producecapsules the permeability of which limit entry of immune cells,antibodies, and cytokines into the capsule. Since different cell typeshave different metabolic requirements, the permeability of the membranecan be optimized based on the cell type encapsulated in the hydrogel.The diameter of the capsules is an important factor that influences boththe immune response towards the cell capsules as well as the masstransport across the capsule membrane.

The growing recognition of the parameters driving fibrosis in vivo hasbeen applied to the analysis of the performance of modified alginates.Intraperitoneal (IP) implantation of modified alginate capsules revealedthat modified alginates may result in abnormally shaped capsules whencrosslinked using conditions defined for unmodified alginates. Theseabnormally shaped capsules can complicate implementation andinterpretation of modified alginate capsules implanted IP. In an effortto improve the capsule morphology, formulation methods for use withmodified alginate microparticles were developed where modified alginateswere blended with a small amount of high molecular weight alginate.Particles prepared from this mixture yielded particles with improvedmorphology and stability.

The unmodified alginate typically has a weight average molecular weightof about 50,000 Daltons to about 500,000 Daltons; however, unmodifiedalginates having molecular weights can also be used. In someembodiments, the weight average molecular weight is from about 50,000 toabout 250,000 Daltons, more preferably from about 50,000 to about150,000 Daltons. In some embodiments, the weight average molecularweight is about 100,000 Daltons.

In other embodiments, one or more additional hydrogel-forming polymersare used in combination with unmodified alginate or in place ofunmodified alginate. Such polymers are known in the art. Examplesinclude, but are not limited to, PEG, chitosan, dextran, hyaluronicacid, silk, fibrin, poly(vinyl alcohol) and poly(hydroxyl ethylmethacrylate).

In some embodiments, the alginate is made up of β-D-mannuronic acid (M)and α-L-guluronic acid (G) linked together. In some embodiments,alginate is a high guluronic acid (G) alginate. In some embodiments, thealginate is a high mannuronic acid (M) alginate. In some embodiments,the ratio of M:G is about 1. In some embodiments, the ratio of M:G isless than 1. In some embodiments, the ratio of M:G is greater than 1.

For example, particles prepared from modified alginate 263_A12microparticles formulated with barium and mannitol were compared toparticles prepared from 263_A12 blended with a small amount ofunmodified SLG100 alginate (16% by weight). The particles prepared froma mixture of modified alginate and unmodified alginate produced morehomogenous microparticle populations in terms of shape and size asevaluated by scanning electron microscopy (SEM). Quantitativefluorescence analysis with prosense at several time points with modifiedalginates blended with SLG100 showed that several reformulated modifiedalginates display less inflammatory response at day 7 compared to thecontrol alginate. Initial experiments with large capsules (1.5 mmdiameter) were comparably clean capsules after 2 weeks in the IP spaceof immunocompetent C57BL6 mice. Subsequent experiments (Example 9) showthat encapsulated human cells can achieve glucose-responsive, long-termglycemic correction (over 170 days) in an immune-competent diabeticanimal with no immunosuppression. This result was accomplished using amodified alginate as disclosed to encapsulate the human cells. Theresulting capsule mitigates immunological responses to human cellimplants, effectively delaying the fibrotic deposition that leads toimplant tissue necrosis. This formulation provided sufficientimmunoprotection to enable long-term glycemic correction, in spite ofthe xenogeneic stimulation that these human cells manifest in animmunocompetent rodent recipient.

In some embodiments, the hydrogel capsules can have any suitable shape.Useful shapes include spheres, sphere-like shapes, spheroids,spheroid-like shapes, ellipsoids, ellipsoid-like shapes, stadiumoids,stadiumoid-like shapes, disks, disk-like shapes, cylinders,cylinder-like shapes, rods, rod-like shapes, cubes, cube-like shapes,cuboids, cuboid-like shapes, toruses, torus-like shapes, and flat andcurved surfaces. Products, devices, and surfaces that have been or willbe coated can have any of these shapes or any shape suitable for theproduct or device.

Spheres, spheroids, and ellipsoids are shapes with curved surfaces thatcan be defined by rotation of circles, ellipses, or a combination aroundeach of the three perpendicular axes, a, b, and c. For a sphere, thethree axes are the same length. For oblate spheroids (also referred toas oblate ellipsoids of rotation), the length of the axes are a=b>c. Forprolate spheroids (also referred to as prolate ellipsoids of rotation),the length of the axes are a=b<c. For tri-axial ellipsoids (alsoreferred to as scalene ellipsoids), the length of the axes are a>b>c.Stadiumoids are rotational shapes of stadiums. Cylinders are rotationalshapes of rectangles rotated on the long axis. Disks are squashedcylinders where the diameter is greater than the height. Rods areelongated cylinders where the long axis is ten or more times thediameter.

“Sphere-like shape,” “spheroid-like shape,” “ellipsoid-like shape,”“stadiumoid-like shape,” “cylinder-like shape,” “rod-like shape,”“cube-like shape,” “cuboid-like shape,” and “torus-like shape” refers toan object having a surface that roughly forms a sphere, spheroid,ellipsoid, stadiumoid, cylinder, rod, cube, cuboid, or torus,respectively. Beyond a perfect or classical form of the shape, asphere-like shape, spheroid-like shape, ellipsoid-like shape,stadiumoid-like shape, cylinder-like shape, rod-like shape, cube-likeshape, cuboid-like shape, and torus-like shape can have waves andundulations.

Generally, a sphere-like shape is an ellipsoid (for its averagedsurface) with semi-principal axes within 10% of each other. The diameterof a sphere or sphere-like shape is the average diameter, such as theaverage of the semi-principal axes. Generally, a spheroid-like shape isan ellipsoid (for its averaged surface) with semi-principal axes within100% of each other. The diameter of a spheroid or spheroid-like shape isthe average diameter, such as the average of the semi-principal axes.Generally, an ellipsoid-like shape is an ellipsoid (for its averagedsurface) with semi-principal axes within 100% of each other. Thediameter of an ellipsoid or ellipsoid-like shape is the averagediameter, such as the average of the semi-principal axes. Generally, astadiumoid-like shape is a stadiumoid (for its averaged surface) withsemi-principal axes of the ends within 20% of each other. The diameterof a stadiumoid or stadiumoid-like shape is the average diameter, suchas the average of the semi-principal axes. Alternatively, the size of astadiumoid or stadiumoid-like shape can be given as the average of thelong axis. Generally, a cylinder-like shape is a cylinder (for itsaveraged surface) with semi-principal axes within 20% of each other. Thediameter of a cylinder or cylinder-like shape is the average diameter,such as the average of the semi-principal axes. Alternatively, the sizeof a cylinder or cylinder-like shape can be given as the average of thelong axis. Generally, a rod-like shape is a rod (for its averagedsurface) with semi-principal axes within 10% of each other. The diameterof a rod or rod-like shape is the average diameter, such as the averageof the semi-principal axes. Alternatively, the size of a rod or rod-likeshape can be given as the average of the long axis. Generally, acube-like shape is a cube (for its averaged surface) with sides within10% of each other. The diameter of a cube or cube-like shape is theaverage side length. Generally, a cuboid-like shape is a cuboid (for itsaveraged surface) with matching sides within 10% of each other. Thediameter of a cuboid or cuboid-like shape is the average side length.Generally, a torus-like shape is a torus (for its averaged surface) withsemi-principal axes within 10% of each other. The diameter of atoms ortorus-like shape is the average diameter, such as the average of thesemi-principal axes. Alternatively, the size of a torus or toms-likeshape can be given as the diameter across the ring.

“Flat side” refers to a contiguous area of more than 5% of a surfacethat has a curvature of 0.

“Sharp angle” refers to a location on a surface across which the tangentto the surface changes by more than 10% over a distance of 2% or less ofthe circumference of the surface. Edges, corners, grooves, and ridges ina surface are all forms of sharp angles.

Preferred capsules can be made of biocompatible materials, have adiameter of at least 1 mm and less than 10 mm, has a spheroid-likeshape, and have one or more of the additional characteristics: surfacepores of the capsules greater than 0 nm and less than 10 μm; surface ofthe capsules neutral or hydrophilic; curvature of the surface of thecapsules at least 0.2 and is not greater than 2 on all points of thesurface; and surface of the capsules lacking flat sides, sharp angles,grooves, or ridges. Generally, the capsules elicit less of a fibroticreaction after implantation than the same capsules lacking one or moreof these characteristics that are present on the capsules.

In some embodiments, the capsule s are provided as a preparation and atleast 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95% or 100% of the capsules in the preparation have a shapecharacteristic described herein, e.g., have a spheroid-like shape, orhave a curvature of the surface of at least 0.2 to 2.0 on all points ofthe surface.

In some embodiments, the hydrogel capsules have a mean diameter that isgreater than 1 mm, preferably 1.5 mm or greater. In some embodiments,the hydrogel capsules can be as large as 8 mm in diameter. For example,the hydrogel capsules is in a size range of 1 mm to 8 mm, 1 mm to 6 mm,1 mm to 5 mm, 1 mm to 4 mm, 1 mm to 3 mm, 1 mm to 2 mm, 1 mm to 1.5 mm,1.5 mm to 8 mm, 1.5 mm to 6 mm, 1.5 mm to 5 mm, 1.5 mm to 4 mm, 1.5 mmto 3 mm, 1.5 mm to 2 mm, 2 mm to 8 mm, 2 mm to 7 mm, 2 mm to 6 mm, 2 mmto 5 mm, 2 mm to 4 mm, 2 mm to 3 mm, 2.5 mm to 8 mm, 2.5 mm to 7 mm, 2.5mm to 6 mm, 2.5 mm to 5 mm, 2.5 mm to 4 mm, 2.5 mm to 3 mm, 3 mm to 8mm, 3 mm to 7 mm, 3 mm to 6 mm, 3 mm to 5 mm, 3 mm to 4 mm, 3.5 mm to 8mm, 3.5 mm to 7 mm, 3.5 mm to 6 mm, 3.5 mm to 5 mm, 3.5 mm to 4 mm, 4 mmto 8 mm, 4 mm to 7 mm, 4 mm to 6 mm, 4 mm to 5 mm, 4.5 mm to 8 mm, 4.5mm to 7 mm, 4.5 mm to 6 mm, 4.5 mm to 5 mm, 5 mm to 8 mm, 5 mm to 7 mm,5 mm to 6 mm, 5.5 mm to 8 mm, 5.5 mm to 7 mm, 5.5 mm to 6 mm, 6 mm to 8mm, 6 mm to 7 mm, 6.5 mm to 8 mm, 6.5 mm to 7 mm, 7 mm to 8 mm, or 7.5mm to 8 mm. In some embodiments, the capsule has a mean diameter or sizebetween 1 mm to 8 mm. In some embodiments, the capsule has a meandiameter or size between 1 mm to 4 mm. In some embodiments, the capsulehas a mean diameter or size between 1 mm to 2 mm.

In some embodiments, the capsules are provided as a preparation and atleast 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95% or 100% of the hydrogel capsules in the preparation have a diameterin a size range described herein

In some embodiments, the hydrogel capsules have a mean pore size rangingfrom 0.1 μm to 10 μm. For example, the pores is in a size range of 0.1μm to 10 μm, 0.1 μm to 9 μm, 0.1 μm to 8 μm, 0.1 μm to 7 μm, 0.1 μm to 6μm, 0.1 μm to 5 μm, 0.1 μm to 4 μm, 0.1 μm to 3 μm, 0.1 μm to 2 μm, 0.15μm to 10 μm, 0.15 μm to 9 μm, 0.15 μm to 8 μm, 0.15 μm to 7 μm, 0.15 μmto 6 μm, 0.15 μm to 5 μm, 0.15 μm to 4 μm, 0.15 μm to 3 μm, 0.15 μm to 2μm, 0.2 μm to 10 μm, 0.2 μm to 9 μm, 0.2 μm to 8 μm, 0.2 μm to 7 μm, 0.2μm to 6 μm, 0.2 μm to 5 μm, 0.2 μm to 4 μm, 0.2 μm to 3 μm, 0.25 μm to10 μm, 0.25 μm to 9 μm, 0.25 μm to 8 μm, 0.25 μm to 7 μm, 0.25 μm to 6μm, 0.25 μm to μm, 0.25 μm to 4 μm, 0.25 μm to 3 μm, 0.3 μm to 10 μm,0.3 μm to 9 μm, 0.3 μm to 8 μm, 0.3 μm to 7 μm, 0.3 μm to 6 μm, 0.3 μmto 5 μm, 0.3 μm to 4 μm, 0.35 μm to 10 μm, 0.35 μm to 9 μm, 0.35 μm to 8μm, 0.35 μm to 7 μm, 0.35 μm to 6 μm, 0.35 μm to μm, 0.35 μm to 4 μm,0.4 μm to 10 μm, 0.4 μm to 9 μm, 0.4 μm to 8 μm, 0.4 μm to 7 μm, 0.4 μmto 6 μm, 0.4 μm to 5 μm, 0.45 μm to 10 μm, 0.45 μm to 9 μm, 0.45 μm to 8μm, 0.45 μm to 7 μm, 0.45 μm to 6 μm, 0.45 μm to 5 μm, 0.5 μm to 10 μm,0.5 μm to 9 μm, 0.5 μm to 8 μm, 0.5 μm to 7 μm, 0.5 μm to 6 μm, 0.55 μmto 10 μm, 0.55 μm to 9 μm, 0.55 μm to 8 μm, 0.55 μm to 7 μm, 0.55 μm to6 μm, 0.6 μm to 10 μm, 0.6 μm to 9 μm, 0.6 μm to 8 μm, 0.6 μm to 7 μm,0.65 μm to 10 μm, 0.65 μm to 9 μm, 0.65 μm to 8 μm, 0.65 μm to 7 μm, 0.7μm to 10 μm, 0.7 μm to 9 μm, 0.7 μm to 8 μm, 0.75 μm to 10 μm, 0.75 μmto 9 μm, 0.75 μm to 8 μm, 0.8 μm to 10 μm, 0.8 μm to 9 μm, 0.85 μm toμm, 0.85 μm to 9 μm, 0.9 μm to 10 μm, 0.95 μm to 10 μm, 1 μm to 10 μm, 1μm to 9 μm, 1 μm to 8 μm, 1 μm to 7 μm, 1 μm to 6 μm, 1 μm to 5 μm, 1 μmto 4 μm, 1 μm to 3 μm, 1 μm to 2 μm, 1.5 μm to 10 μm, 1.5 μm to 9 μm,1.5 μm to 8 μm, 1.5 μm to 7 μm, 1.5 μm to 6 μm, 1.5 μm to 5 μm, 1.5 μmto 4 μm, 1.5 μm to 3 μm, 1.5 μm to 2 μm, 2 μm to 10 μm, 2 μm to 9 μm, 2μm to 8 μm, 2 μm to 7 μm, 2 μm to 6 μm, 2 μm to 5 μm, 2 μm to 4 μm, 2 μmto 3 μm, 2.5 μm to 10 μm, 2.5 μm to 9 μm, 2.5 μm to 8 μm, 2.5 μm to 7μm, 2.5 μm to 6 μm, 2.5 μm to 5 μm, 2.5 μm to 4 μm, 2.5 μm to 3 μm, 3 μmto 10 μm, 3 μm to 9 μm, 3 μm to 8 μm, 3 μm to 7 μm, 3 μm to 6 μm, 3 μmto 5 μm, 3 μm to 4 μm, 3.5 μm to 10 μm, 3.5 μm to 9 μm, 3.5 μm to 8 μm,3.5 μm to 7 μm, 3.5 μm to 6 μm, 3.5 μm to 5 μm, 3.5 μm to 4 μm, 4 μm to10 μm, 4 μm to 9 μm, 4 μm to 8 μm, 4 μm to 7 μm, 4 μm to 6 μm, 4 μm to 5μm, 4.5 μm to 10 μm, 4.5 μm to 9 μm, 4.5 μm to 8 μm, 4.5 μm to 7 μm, 4.5μm to 6 μm, 4.5 μm to 5 μm, 5 μm to 10 μm, 5 μm to 9 μm, 5 μm to 8 μm, 5μm to 7 μm, 5 μm to 6 μm, 5.5 μm to 10 μm, 5.5 μm to 9 μm, 5.5 μm to 8μm, 5.5 μm to 7 μm, 5.5 μm to 6 μm, 6 μm to 10 μm, 6 μm to 9 μm, 6 μm to8 μm, 6 μm to 7 μm, 6.5 μm to 10 μm, 6.5 μm to 9 μm, 6.5 μm to 8 μm, 6.5μm to 7 μm, 7 μm to 10 μm, 7 μm to 9 μm, 7 μm to 8 μm, 7.5 μm to 10 μm,7.5 μm to 9 μm, 7.5 μm to 8 μm, 8 μm to μm, 8 μm to 9 μm, 8.5 μm to 10μm, 8.5 μm to 9 μm, 9 μm to 10 μm, or 9.5 μm to 10 μm. In someembodiments, the capsule has a mean pore size ranging from 0.1 μm to 10μm. In some embodiments, the capsule has a mean pore size ranging from0.1 μm to 5 μm. In some embodiments, the capsule has a mean pore sizeranging from 0.1 μm to 1 μm.

In some embodiments, the capsules are provided as a preparation and atleast 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95% or 100% of the hydrogel capsules in the preparation have pores in asize range described herein.

In some embodiments, the chemical modifications of the residues withinthe hydrogel capsules are expressed as a density, i.e., average numberof attached modifications per given area. In some embodiments, thedensity is at least, is less than, or is 0.1, 0.2, 0.5, 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40,45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140,150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280,290, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 550, 600,650, 700, 750, 800, 850, 900, or 1000 chemical modifications per μm² onthe surface of the hydrogel capsules, in the interior of the hydrogelcapsules, or both. In some embodiments, the density is at least 100chemical derivatizations per μm² on the surface of the hydrogelcapsules, in the interior of the hydrogel capsules, or both. In someembodiments, the density is at least 1000 chemical derivatizations perμm² on the surface of the hydrogel capsules, in the interior of thehydrogel capsules, or both.

In some embodiments the density is in the range of 0.1 to 0.2, 0.1 to0.5, 0.1 to 1, 0.1 to 2, 0.1 to 3, 0.1 to 4, 0.1 to 5, 0.1 to 6, 0.1 to7, 0.1 to 8, 0.1 to 9, 0.1 to 10, 0.1 to 11, 0.1 to 12, 0.1 to 13, 0.1to 14, 0.1 to 15, 0.1 to 16, 0.1 to 17, 0.1 to 18, 0.1 to 19, 0.1 to 20,0.1 to 25, 0.1 to 30, 0.1 to 35, 0.1 to 40, 0.1 to 45, 0.1 to 50, 0.1 to55, 0.1 to 60, 0.1 to 65, 0.1 to 70, 0.1 to 75, 0.1 to 80, 0.1 to 85,0.1 to 90, 0.1 to 95, 0.1 to 100, 0.1 to 110, 0.1 to 120, 0.1 to 130,0.1 to 140, 0.1 to 150, 0.1 to 160, 0.1 to 170, 0.1 to 180, 0.1 to 190,0.1 to 200, 0.1 to 210, 0.1 to 220, 0.1 to 230, 0.1 to 240, 0.1 to 250,0.1 to 260, 0.1 to 270, 0.1 to 280, 0.1 to 290, 0.1 to 300, 0.1 to 320,0.1 to 340, 0.1 to 360, 0.1 to 380, 0.1 to 400, 0.1 to 420, 0.1 to 440,0.1 to 460, 0.1 to 480, 0.1 to 500, 0.1 to 550, 0.1 to 600, 0.1 to 650,0.1 to 700, 0.1 to 750, 0.1 to 800, 0.1 to 850, 0.1 to 900, and 0.1 to1000 chemical derivatizations per μm² on the surface of the hydrogelcapsules, in the interior of the hydrogel capsules, or both.

In some embodiments the density is in the range of 0.2 to 0.5, 0.0 to 1,0.2 to 2, 0.2 to 3, 0.2 to 4, 0.2 to 5, 0.2 to 6, 0.2 to 7, 0.2 to 8,0.2 to 9, 0.2 to 10, 0.2 to 11, 0.2 to 12, 0.2 to 13, 0.2 to 14, 0.2 to15, 0.2 to 16, 0.2 to 17, 0.2 to 18, 0.2 to 19, 0.2 to 20, 0.2 to 25,0.2 to 30, 0.2 to 35, 0.2 to 40, 0.2 to 45, 0.2 to 50, 0.2 to 55, 0.2 to60, 0.2 to 65, 0.2 to 70, 0.2 to 75, 0.2 to 80, 0.2 to 85, 0.2 to 90,0.2 to 95, 0.2 to 100, 0.2 to 110, 0.2 to 120, 0.2 to 130, 0.2 to 140,0.2 to 150, 0.2 to 160, 0.2 to 170, 0.2 to 180, 0.2 to 190, 0.2 to 200,0.2 to 210, 0.2 to 220, 0.2 to 230, 0.2 to 240, 0.2 to 250, 0.2 to 260,0.2 to 270, 0.2 to 280, 0.2 to 290, 0.2 to 300, 0.2 to 320, 0.2 to 340,0.2 to 360, 0.2 to 380, 0.2 to 400, 0.2 to 420, 0.2 to 440, 0.2 to 460,0.2 to 480, 0.2 to 500, 0.2 to 550, 0.2 to 600, 0.2 to 650, 0.2 to 700,0.2 to 750, 0.2 to 800, 0.2 to 850, 0.2 to 900, and 0.2 to 1000 chemicalderivatizations per μm² on the surface of the hydrogel capsules, in theinterior of the hydrogel capsules, or both.

In some embodiments the density is in the range of 0.5 to 1, 0.5 to 2,0.5 to 3, 0.5 to 4, 0.5 to 5, 0.5 to 6, 0.5 to 7, 0.5 to 8, 0.5 to 9,0.5 to 10, 0.5 to 11, 0.5 to 12, 0.5 to 13, 0.5 to 14, 0.5 to 15, 0.5 to16, 0.5 to 17, 0.5 to 18, 0.5 to 19, 0.5 to 20, 0.5 to 25, 0.5 to 30,0.5 to 35, 0.5 to 40, 0.5 to 45, 0.5 to 50, 0.5 to 55, 0.5 to 60, 0.5 to65, 0.5 to 70, 0.5 to 75, 0.5 to 80, 0.5 to 85, 0.5 to 90, 0.5 to 95,0.5 to 100, 0.5 to 110, 0.5 to 120, 0.5 to 130, 0.5 to 140, 0.5 to 150,0.5 to 160, 0.5 to 170, 0.5 to 180, 0.5 to 190, 0.5 to 200, 0.5 to 210,0.5 to 220, 0.5 to 230, 0.5 to 240, 0.5 to 250, 0.5 to 260, 0.5 to 270,0.5 to 280, 0.5 to 290, 0.5 to 300, 0.5 to 320, 0.5 to 340, 0.5 to 360,0.5 to 380, 0.5 to 400, 0.5 to 420, 0.5 to 440, 0.5 to 460, 0.5 to 480,0.5 to 500, 0.5 to 550, 0.5 to 600, 0.5 to 650, 0.5 to 700, 0.5 to 750,0.5 to 800, 0.5 to 850, 0.5 to 900, and 0.5 to 1000 chemicalderivatizations per μm² on the surface of the hydrogel capsules, in theinterior of the hydrogel capsules, or both.

In some embodiments the density is in the range of 1 to 2, 1 to 3, 1 to4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 1 to 11, 1 to 12, 1to 13, 1 to 14, 1 to 15, 1 to 16, 1 to 17, 1 to 18, 1 to 19, 1 to 20, 1to 25, 1 to 30, 1 to 35, 1 to 40, 1 to 45, 1 to 50, 1 to 55, 1 to 60, 1to 65, 1 to 70, 1 to 75, 1 to 80, 1 to 85, 1 to 90, 1 to 95, 1 to 100, 1to 110, 1 to 120, 1 to 130, 1 to 140, 1 to 150, 1 to 160, 1 to 170, 1 to180, 1 to 190, 1 to 200, 1 to 210, 1 to 220, 1 to 230, 1 to 240, 1 to250, 1 to 260, 1 to 270, 1 to 280, 1 to 290, 1 to 300, 1 to 320, 1 to340, 1 to 360, 1 to 380, 1 to 400, 1 to 420, 1 to 440, 1 to 460, 1 to480, 1 to 500, 1 to 550, 1 to 600, 1 to 650, 1 to 700, 1 to 750, 1 to800, 1 to 850, 1 to 900, and 1 to 1000 chemical derivatizations per μm²on the surface of the hydrogel capsules, in the interior of the hydrogelcapsules, or both.

In some embodiments the density is in the range of 2 to 3, 2 to 4, 2 to5, 2 to 6, 2 to 7, 2 to 8, 2 to 9, 2 to 10, 2 to 11, 2 to 12, 2 to 13, 2to 14, 2 to 15, 2 to 16, 2 to 17, 2 to 18, 2 to 19, 2 to 20, 2 to 25, 2to 30, 2 to 35, 2 to 40, 2 to 45, 2 to 50, 2 to 55, 2 to 60, 2 to 65, 2to 70, 2 to 75, 2 to 80, 2 to 85, 2 to 90, 2 to 95, 2 to 100, 2 to 110,2 to 120, 2 to 130, 2 to 140, 2 to 150, 2 to 160, 2 to 170, 2 to 180, 2to 190, 2 to 200, 2 to 210, 2 to 220, 2 to 230, 2 to 240, 2 to 250, 2 to260, 2 to 270, 2 to 280, 2 to 290, 2 to 300, 2 to 320, 2 to 340, 2 to360, 2 to 380, 2 to 400, 2 to 420, 2 to 440, 2 to 460, 2 to 480, 2 to500, 2 to 550, 2 to 600, 2 to 650, 2 to 700, 2 to 750, 2 to 800, 2 to850, 2 to 900, and 2 to 1000 chemical derivatizations per μm² on thesurface of the hydrogel capsules, in the interior of the hydrogelcapsules, or both.

In some embodiments the density is in the range of 3 to 4, 3 to 5, 3 to6, 3 to 7, 3 to 8, 3 to 9, 3 to 10, 3 to 11, 3 to 12, 3 to 13, 3 to 14,3 to 15, 3 to 16, 3 to 17, 3 to 18, 3 to 19, 3 to 20, 3 to 25, 3 to 30,3 to 35, 3 to 40, 3 to 45, 3 to 50, 3 to 55, 3 to 60, 3 to 65, 3 to 70,3 to 75, 3 to 80, 3 to 85, 3 to 90, 3 to 95, 3 to 100, 3 to 110, 3 to120, 3 to 130, 3 to 140, 3 to 150, 3 to 160, 3 to 170, 3 to 180, 3 to190, 3 to 200, 3 to 210, 3 to 220, 3 to 230, 3 to 240, 3 to 250, 3 to260, 3 to 270, 3 to 280, 3 to 290, 3 to 300, 3 to 320, 3 to 340, 3 to360, 3 to 380, 3 to 400, 3 to 420, 3 to 440, 3 to 460, 3 to 480, 3 to500, 3 to 550, 3 to 600, 3 to 650, 3 to 700, 3 to 750, 3 to 800, 3 to850, 3 to 900, and 3 to 1000 chemical derivatizations per μm² on thesurface of the hydrogel capsules, in the interior of the hydrogelcapsules, or both.

In some embodiments the density is in the range of 4 to 5, 4 to 6, 4 to7, 4 to 8, 4 to 9, 4 to 10, 4 to 11, 4 to 12, 4 to 13, 4 to 14, 4 to 15,4 to 16, 4 to 17, 4 to 18, 4 to 19, 4 to 20, 4 to 25, 4 to 30, 4 to 35,4 to 40, 4 to 45, 4 to 50, 4 to 55, 4 to 60, 4 to 65, 4 to 70, 4 to 75,4 to 80, 4 to 85, 4 to 90, 4 to 95, 4 to 100, 4 to 110, 4 to 120, 4 to130, 4 to 140, 4 to 150, 4 to 160, 4 to 170, 4 to 180, 4 to 190, 4 to200, 4 to 210, 4 to 220, 4 to 230, 4 to 240, 4 to 250, 4 to 260, 4 to270, 4 to 280, 4 to 290, 4 to 300, 4 to 320, 4 to 340, 4 to 360, 4 to380, 4 to 400, 4 to 420, 4 to 440, 4 to 460, 4 to 480, 4 to 500, 4 to550, 4 to 600, 4 to 650, 4 to 700, 4 to 750, 4 to 800, 4 to 850, 4 to900, and 4 to 1000 chemical derivatizations per μm² on the surface ofthe hydrogel capsules, in the interior of the hydrogel capsules, orboth.

In some embodiments the density is in the range of 5 to 6, 5 to 7, 5 to8, 5 to 9, 5 to 10, 5 to 11, 5 to 12, 5 to 13, 5 to 14, 5 to 15, 5 to16, 5 to 17, 5 to 18, 5 to 19, 5 to 20, 5 to 25, 5 to 30, 5 to 35, 5 to40, 5 to 45, 5 to 50, 5 to 55, 5 to 60, 5 to 65, 5 to 70, 5 to 75, 5 to80, 5 to 85, 5 to 90, 5 to 95, 5 to 100, 5 to 110, 5 to 120, 5 to 130, 5to 140, 5 to 150, 5 to 160, 5 to 170, 5 to 180, 5 to 190, 5 to 200, 5 to210, 5 to 220, 5 to 230, 5 to 240, 5 to 250, 5 to 260, 5 to 270, 5 to280, 5 to 290, 5 to 300, 5 to 320, 5 to 340, 5 to 360, 5 to 380, to 400,5 to 420, 5 to 440, 5 to 460, 5 to 480, 5 to 500, 5 to 550, 5 to 600, 5to 650, 5 to 700, 5 to 750, 5 to 800, 5 to 850, 5 to 900, and 5 to 1000chemical derivatizations per μm² on the surface of the hydrogelcapsules, in the interior of the hydrogel capsules, or both.

In some embodiments the density is in the range of 6 to 7, 6 to 8, 6 to9, 6 to 10, 6 to 11, 6 to 12, 6 to 13, 6 to 14, 6 to 15, 6 to 16, 6 to17, 6 to 18, 6 to 19, 6 to 20, 6 to 25, 6 to 30, 6 to 35, 6 to 40, 6 to45, 6 to 50, 6 to 55, 6 to 60, 6 to 65, 6 to 70, 6 to 75, 6 to 80, 6 to85, 6 to 90, 6 to 95, 6 to 100, 6 to 110, 6 to 120, 6 to 130, 6 to 140,6 to 150, 6 to 160, 6 to 170, 6 to 180, 6 to 190, 6 to 200, 6 to 210, 6to 220, 6 to 230, 6 to 240, 6 to 250, 6 to 260, 6 to 270, 6 to 280, 6 to290, 6 to 300, 6 to 320, 6 to 340, 6 to 360, 6 to 380, 6 to 400, 6 to420, 6 to 440, 6 to 460, 6 to 480, 6 to 500, 6 to 550, 6 to 600, 6 to650, 6 to 700, 6 to 750, 6 to 800, 6 to 850, 6 to 900, and 6 to 1000chemical derivatizations per μm² on the surface of the hydrogelcapsules, in the interior of the hydrogel capsules, or both.

In some embodiments the density is in the range of 7 to 8, 7 to 9, 7 to10, 7 to 11, 7 to 12, 7 to 13, 7 to 14, 7 to 15, 7 to 16, 7 to 17, 7 to18, 7 to 19, 7 to 20, 7 to 25, 7 to 30, 7 to 35, 7 to 40, 7 to 45, 7 to50, 7 to 55, 7 to 60, 7 to 65, 7 to 70, 7 to 75, 7 to 80, 7 to 85, 7 to90, 7 to 95, 7 to 100, 7 to 110, 7 to 120, 7 to 130, 7 to 140, 7 to 150,7 to 160, 7 to 170, 7 to 180, 7 to 190, 7 to 200, 7 to 210, 7 to 220, 7to 230, 7 to 240, 7 to 250, 7 to 260, 7 to 270, 7 to 280, 7 to 290, 7 to300, 7 to 320, 7 to 340, 7 to 360, 7 to 380, 7 to 400, 7 to 420, 7 to440, 7 to 460, 7 to 480, 7 to 500, 7 to 550, 7 to 600, 7 to 650, 7 to700, 7 to 750, 7 to 800, 7 to 850, 7 to 900, and 7 to 1000 chemicalderivatizations per μm² on the surface of the hydrogel capsules, in theinterior of the hydrogel capsules, or both.

In some embodiments the density is in the range of 8 to 9, 8 to 10, 8 to11, 8 to 12, 8 to 13, 8 to 14, 8 to 15, 8 to 16, 8 to 17, 8 to 18, 8 to19, 8 to 20, 8 to 25, 8 to 30, 8 to 35, 8 to 40, 8 to 45, 8 to 50, 8 to55, 8 to 60, 8 to 65, 8 to 70, 8 to 75, 8 to 80, 8 to 85, 8 to 90, 8 to95, 8 to 100, 8 to 110, 8 to 120, 8 to 130, 8 to 140, 8 to 150, 8 to160, 8 to 170, 8 to 180, 8 to 190, 8 to 200, 8 to 210, 8 to 220, 8 to230, 8 to 240, 8 to 250, 8 to 260, 8 to 270, 8 to 280, 8 to 290, 8 to300, 8 to 320, 8 to 340, 8 to 360, 8 to 380, 8 to 400, 8 to 420, 8 to440, 8 to 460, 8 to 480, 8 to 500, 8 to 550, 8 to 600, 8 to 650, 8 to700, 8 to 750, 8 to 800, 8 to 850, 8 to 900, and 8 to 1000 chemicalderivatizations per μm² on the surface of the hydrogel capsules, in theinterior of the hydrogel capsules, or both.

In some embodiments the density is in the range of 9 to 10, 9 to 11, 9to 12, 9 to 13, 9 to 14, 9 to 15, 9 to 16, 9 to 17, 9 to 18, 9 to 19, 9to 20, 9 to 25, 9 to 30, 9 to 35, 9 to 40, 9 to 45, 9 to 50, 9 to 55, 9to 60, 9 to 65, 9 to 70, 9 to 75, 9 to 80, 9 to 85, 9 to 90, 9 to 95, 9to 100, 9 to 110, 9 to 120, 9 to 130, 9 to 140, 9 to 150, 9 to 160, 9 to170, 9 to 180, 9 to 190, 9 to 200, 9 to 210, 9 to 220, 9 to 230, 9 to240, 9 to 250, 9 to 260, 9 to 270, 9 to 280, 9 to 290, 9 to 300, 9 to320, 9 to 340, 9 to 360, 9 to 380, 9 to 400, 9 to 420, 9 to 440, 9 to460, 9 to 480, 9 to 500, 9 to 550, 9 to 600, 9 to 650, 9 to 700, 9 to750, 9 to 800, 9 to 850, 9 to 900, and 9 to 1000 chemicalderivatizations per μm² on the surface of the hydrogel capsules, in theinterior of the hydrogel capsules, or both.

In some embodiments the density is in the range of 10 to 11, 10 to 12,10 to 13, to 14, 10 to 15, 10 to 16, 10 to 17, 10 to 18, 10 to 19, 10 to20, 10 to 25, 10 to 30, 10 to 35, 10 to 40, 10 to 45, 10 to 50, 10 to55, 10 to 60, 10 to 65, 10 to 70, 10 to 75, 10 to 80, 10 to 85, 10 to90, 10 to 95, 10 to 100, 10 to 110, 10 to 120, 10 to 130, 10 to 140, 10to 150, 10 to 160, 10 to 170, 10 to 180, 10 to 190, 10 to 200, 10 to210, 10 to 220, 10 to 230, 10 to 240, 10 to 250, 10 to 260, 10 to 270,10 to 280, 10 to 290, 10 to 300, 10 to 320, 10 to 340, 10 to 360, 10 to380, 10 to 400, 10 to 420, 10 to 440, 10 to 460, 10 to 480, 10 to 500,10 to 550, 10 to 600, 10 to 650, 10 to 700, 10 to 750, 10 to 800, 10 to850, 10 to 900, and 10 to 1000 chemical derivatizations per μm² on thesurface of the hydrogel capsules, in the interior of the hydrogelcapsules, or both.

In some embodiments the density is in the range of 20 to 25, 20 to 30,20 to 35, to 40, 20 to 45, 20 to 50, 20 to 55, 20 to 60, 20 to 65, 20 to70, 20 to 75, 20 to 80, 20 to 85, 20 to 90, 20 to 95, 20 to 100, 20 to110, 20 to 120, 20 to 130, 20 to 140, 20 to 150, to 160, 20 to 170, 20to 180, 20 to 190, 20 to 200, 20 to 210, 20 to 220, 20 to 230, 20 to240, 20 to 250, 20 to 260, 20 to 270, 20 to 280, 20 to 290, 20 to 300,20 to 320, 20 to 340, 20 to 360, 20 to 380, 20 to 400, 20 to 420, 20 to440, 20 to 460, 20 to 480, 20 to 500, 20 to 550, 20 to 600, 20 to 650,20 to 700, 20 to 750, 20 to 800, 20 to 850, 20 to 900, and 20 to 1000chemical derivatizations per μm² on the surface of the hydrogelcapsules, in the interior of the hydrogel capsules, or both.

In some embodiments the density is in the range of 30 to 35, 30 to 40,30 to 45, to 50, 30 to 55, 30 to 60, 30 to 65, 30 to 70, 30 to 75, 30 to80, 30 to 85, 30 to 90, 30 to 95, 30 to 100, 30 to 110, 30 to 120, 30 to130, 30 to 140, 30 to 150, 30 to 160, 30 to 170, 30 to 180, 30 to 190,30 to 200, 30 to 210, 30 to 220, 30 to 230, 30 to 240, 30 to 250, 30 to260, 30 to 270, 30 to 280, 30 to 290, 30 to 300, 30 to 320, 30 to 340,30 to 360, 30 to 380, 30 to 400, 30 to 420, 30 to 440, 30 to 460, 30 to480, 30 to 500, 30 to 550, 30 to 600, 30 to 650, 30 to 700, 30 to 750,30 to 800, 30 to 850, 30 to 900, and 30 to 1000 chemical derivatizationsper μm² on the surface of the hydrogel capsules, in the interior of thehydrogel capsules, or both.

In some embodiments the density is in the range of 40 to 45, 40 to 50,40 to 55, to 60, 40 to 65, 40 to 70, 40 to 75, 40 to 80, 40 to 85, 40 to90, 40 to 95, 40 to 100, 40 to 110, 40 to 120, 40 to 130, 40 to 140, 40to 150, 40 to 160, 40 to 170, 40 to 180, 40 to 190, 40 to 200, 40 to210, 40 to 220, 40 to 230, 40 to 240, 40 to 250, 40 to 260, 40 to 270,40 to 280, 40 to 290, 40 to 300, 40 to 320, 40 to 340, 40 to 360, 40 to380, 40 to 400, 40 to 420, 40 to 440, 40 to 460, 40 to 480, 40 to 500,40 to 550, 40 to 600, 40 to 650, 40 to 700, 40 to 750, 40 to 800, 40 to850, 40 to 900, and 40 to 1000 chemical derivatizations per μm² on thesurface of the hydrogel capsules, in the interior of the hydrogelcapsules, or both.

In some embodiments the density is in the range of 50 to 55, 50 to 60,50 to 65, 50 to 70, 50 to 75, 50 to 80, 50 to 85, 50 to 90, 50 to 95, 50to 100, 50 to 110, 50 to 120, 50 to 130, 50 to 140, 50 to 150, 50 to160, 50 to 170, 50 to 180, 50 to 190, 50 to 200, 50 to 210, 50 to 220,50 to 230, 50 to 240, 50 to 250, 50 to 260, 50 to 270, 50 to 280, 50 to290, 50 to 300, 50 to 320, 50 to 340, 50 to 360, 50 to 380, 50 to 400,50 to 420, 50 to 440, 50 to 460, 50 to 480, 50 to 500, 50 to 550, 50 to600, 50 to 650, 50 to 700, 50 to 750, 50 to 800, 50 to 850, 50 to 900,and 50 to 1000 chemical derivatizations per μm² on the surface of thehydrogel capsules, in the interior of the hydrogel capsules, or both.

In some embodiments the density is in the range of 60 to 65, 60 to 70,60 to 75, 60 to 80, 60 to 85, 60 to 90, 60 to 95, 60 to 100, 60 to 110,60 to 120, 60 to 130, 60 to 140, 60 to 150, 60 to 160, 60 to 170, 60 to180, 60 to 190, 60 to 200, 60 to 210, 60 to 220, 60 to 230, 60 to 240,60 to 250, 60 to 260, 60 to 270, 60 to 280, 60 to 290, 60 to 300, 60 to320, 60 to 340, 60 to 360, 60 to 380, 60 to 400, 60 to 420, 60 to 440,60 to 460, 60 to 480, 60 to 500, 60 to 550, 60 to 600, 60 to 650, 60 to700, 60 to 750, 60 to 800, 60 to 850, 60 to 900, and 60 to 1000 chemicalderivatizations per μm² on the surface of the hydrogel capsules, in theinterior of the hydrogel capsules, or both.

In some embodiments the density is in the range of 70 to 75, 70 to 80,70 to 85, 70 to 90, 70 to 95, 70 to 100, 70 to 110, 70 to 120, 70 to130, 70 to 140, 70 to 150, 70 to 160, 70 to 170, 70 to 180, 70 to 190,70 to 200, 70 to 210, 70 to 220, 70 to 230, 70 to 240, 70 to 250, 70 to260, 70 to 270, 70 to 280, 70 to 290, 70 to 300, 70 to 320, 70 to 340,70 to 360, 70 to 380, 70 to 400, 70 to 420, 70 to 440, 70 to 460, 70 to480, 70 to 500, 70 to 550, 70 to 600, 70 to 650, 70 to 700, 70 to 750,70 to 800, 70 to 850, 70 to 900, and 70 to 1000 chemical derivatizationsper μm² on the surface of the hydrogel capsules, in the interior of thehydrogel capsules, or both.

In some embodiments the density is in the range of 80 to 85, 80 to 90,80 to 95, 80 to 100, 80 to 110, 80 to 120, 80 to 130, 80 to 140, 80 to150, 80 to 160, 80 to 170, 80 to 180, 80 to 190, 80 to 200, 80 to 210,80 to 220, 80 to 230, 80 to 240, 80 to 250, 80 to 260, 80 to 270, 80 to280, 80 to 290, 80 to 300, 80 to 320, 80 to 340, 80 to 360, 80 to 380,80 to 400, 80 to 420, 80 to 440, 80 to 460, 80 to 480, 80 to 500, 80 to550, 80 to 600, 80 to 650, 80 to 700, 80 to 750, 80 to 800, 80 to 850,80 to 900, and 80 to 1000 chemical derivatizations per μm² on thesurface of the hydrogel capsules, in the interior of the hydrogelcapsules, or both.

In some embodiments the density is in the range of 90 to 95, 90 to 100,90 to 110, 90 to 120, 90 to 130, 90 to 140, 90 to 150, 90 to 160, 90 to170, 90 to 180, 90 to 190, 90 to 200, 90 to 210, 90 to 220, 90 to 230,90 to 240, 90 to 250, 90 to 260, 90 to 270, 90 to 280, 90 to 290, 90 to300, 90 to 320, 90 to 340, 90 to 360, 90 to 380, 90 to 400, 90 to 420,90 to 440, 90 to 460, 90 to 480, 90 to 500, 90 to 550, 90 to 600, 90 to650, 90 to 700, 90 to 750, 90 to 800, 90 to 850, 90 to 900, and 90 to1000 chemical derivatizations per μm² on the surface of the hydrogelcapsules, in the interior of the hydrogel capsules, or both.

In some embodiments the density is in the range of 100 to 110, 100 to120, 100 to 130, 100 to 140, 100 to 150, 100 to 160, 100 to 170, 100 to180, 100 to 190, 100 to 200, 100 to 210, 100 to 220, 100 to 230, 100 to240, 100 to 250, 100 to 260, 100 to 270, 100 to 280, 100 to 290, 100 to300, 100 to 320, 100 to 340, 100 to 360, 100 to 380, 100 to 400, 100 to420, 100 to 440, 100 to 460, 100 to 480, 100 to 500, 100 to 550, 100 to600, 100 to 650, 100 to 700, 100 to 750, 100 to 800, 100 to 850, 100 to900, and 100 to 1000 chemical derivatizations per μm² on the surface ofthe hydrogel capsules, in the interior of the hydrogel capsules, orboth.

In some embodiments the density is in the range of 200 to 210, 200 to220, 200 to 230, 200 to 240, 200 to 250, 200 to 260, 200 to 270, 200 to280, 200 to 290, 200 to 300, 200 to 320, 200 to 340, 200 to 360, 200 to380, 200 to 400, 200 to 420, 200 to 440, 200 to 460, 200 to 480, 200 to500, 200 to 550, 200 to 600, 200 to 650, 200 to 700, 200 to 750, 200 to800, 200 to 850, 200 to 900, and 200 to 1000 chemical derivatizationsper μm² on the surface of the hydrogel capsules, in the interior of thehydrogel capsules, or both.

In some embodiments the density is in the range of 300 to 320, 300 to340, 300 to 360, 300 to 380, 300 to 400, 300 to 420, 300 to 440, 300 to460, 300 to 480, 300 to 500, 300 to 550, 300 to 600, 300 to 650, 300 to700, 300 to 750, 300 to 800, 300 to 850, 300 to 900, and 300 to 1000chemical derivatizations per μm² on the surface of the hydrogelcapsules, in the interior of the hydrogel capsules, or both.

In some embodiments the density is in the range of 400 to 420, 400 to440, 400 to 460, 400 to 480, 400 to 500, 400 to 550, 400 to 600, 400 to650, 400 to 700, 400 to 750, 400 to 800, 400 to 850, 400 to 900, and 400to 1000 chemical derivatizations per μm² on the surface of the hydrogelcapsules, in the interior of the hydrogel capsules, or both.

In some embodiments the density is in the range of 500 to 550, 500 to600, 500 to 650, 500 to 700, 500 to 750, 500 to 800, 500 to 850, 500 to900, and 500 to 1000 chemical derivatizations per μm² on the surface ofthe hydrogel capsules, in the interior of the hydrogel capsules, orboth.

In some embodiments the density is in the range of 600 to 650, 600 to700, 600 to 750, 600 to 800, 600 to 850, 600 to 900, and 600 to 1000chemical derivatizations per μm² on the surface of the hydrogelcapsules, in the interior of the hydrogel capsules, or both.

In some embodiments the density is in the range of 700 to 750, 700 to800, 700 to 850, 700 to 900, and 700 to 1000 chemical derivatizationsper μm² on the surface of the hydrogel capsules, in the interior of thehydrogel capsules, or both.

In some embodiments the density is in the range of 800 to 850, 800 to900, and 800 to 1000 chemical derivatizations per μm² on the surface ofthe hydrogel capsules, in the interior of the hydrogel capsules, orboth.

In some embodiments the density is in the range of 900 to 1000 chemicalderivatizations per μm² on the surface of the hydrogel capsules, in theinterior of the hydrogel capsules, or both.

In some embodiments, the capsules are provided as a preparation and atleast 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95% or 100% of the capsules in the preparation have a combination ofdiameter and pore size described herein.

In some embodiments, density chemical derivatizations of the surface ofthe capsules or products are expressed as a percent surfacemodifications or concentration of surface modifications. In someembodiments, the concentration of surface modifications is at least, isless than, or is 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30,35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, and 100 percent.

In some embodiments the concentration of surface modifications is in therange of 0.1 to 0.2, 0.1 to 0.5, 0.1 to 1, 0.1 to 2, 0.1 to 3, 0.1 to 4,0.1 to 5, 0.1 to 6, 0.1 to 7, 0.1 to 8, 0.1 to 9, 0.1 to 10, 0.1 to 11,0.1 to 12, 0.1 to 13, 0.1 to 14, 0.1 to 15, 0.1 to 16, 0.1 to 17, 0.1 to18, 0.1 to 19, 0.1 to 20, 0.1 to 25, 0.1 to 30, 0.1 to 35, 0.1 to 40,0.1 to 45, 0.1 to 50, 0.1 to 55, 0.1 to 60, 0.1 to 65, 0.1 to 70, 0.1 to75, 0.1 to 80, 0.1 to 85, 0.1 to 90, 0.1 to 95, 0.1 to 100 percentsurface modifications.

In some embodiments the concentration of surface modifications is in therange of 0.2 to 0.5, 0.0 to 1, 0.2 to 2, 0.2 to 3, 0.2 to 4, 0.2 to 5,0.2 to 6, 0.2 to 7, 0.2 to 8, 0.2 to 9, 0.2 to 10, 0.2 to 11, 0.2 to 12,0.2 to 13, 0.2 to 14, 0.2 to 15, 0.2 to 16, 0.2 to 17, 0.2 to 18, 0.2 to19, 0.2 to 20, 0.2 to 25, 0.2 to 30, 0.2 to 35, 0.2 to 40, 0.2 to 45,0.2 to 50, 0.2 to 55, 0.2 to 60, 0.2 to 65, 0.2 to 70, 0.2 to 75, 0.2 to80, 0.2 to 85, 0.2 to 90, 0.2 to 95, 0.2 to 100 percent surfacemodifications.

In some embodiments the concentration of surface modifications is in therange of 0.5 to 1, 0.5 to 2, 0.5 to 3, 0.5 to 4, 0.5 to 5, 0.5 to 6, 0.5to 7, 0.5 to 8, 0.5 to 9, 0.5 to 10, 0.5 to 11, 0.5 to 12, 0.5 to 13,0.5 to 14, 0.5 to 15, 0.5 to 16, 0.5 to 17, 0.5 to 18, 0.5 to 19, 0.5 to20, 0.5 to 25, 0.5 to 30, 0.5 to 35, 0.5 to 40, 0.5 to 45, 0.5 to 50,0.5 to 55, 0.5 to 60, 0.5 to 65, 0.5 to 70, 0.5 to 75, 0.5 to 80, 0.5 to85, 0.5 to 90, 0.5 to 95, 0.5 to 100 percent surface modifications.

In some embodiments the concentration of surface modifications is in therange of 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9,1 to 10, 1 to 11, 1 to 12, 1 to 13, 1 to 14, 1 to 15, 1 to 16, 1 to 17,1 to 18, 1 to 19, 1 to 20, 1 to 25, 1 to 30, 1 to 35, 1 to 40, 1 to 45,1 to 50, 1 to 55, 1 to 60, 1 to 65, 1 to 70, 1 to 75, 1 to 80, 1 to 85,1 to 90, 1 to 95, 1 to 100 percent surface modifications.

In some embodiments the concentration of surface modifications is in therange of 2 to 3, 2 to 4, 2 to 5, 2 to 6, 2 to 7, 2 to 8, 2 to 9, 2 to10, 2 to 11, 2 to 12, 2 to 13, 2 to 14, 2 to 15, 2 to 16, 2 to 17, 2 to18, 2 to 19, 2 to 20, 2 to 25, 2 to 30, 2 to 35, 2 to 40, 2 to 45, 2 to50, 2 to 55, 2 to 60, 2 to 65, 2 to 70, 2 to 75, 2 to 80, 2 to 85, 2 to90, 2 to 95, 2 to 100 percent surface modifications.

In some embodiments the concentration of surface modifications is in therange of 3 to 4, 3 to 5, 3 to 6, 3 to 7, 3 to 8, 3 to 9, 3 to 10, 3 to11, 3 to 12, 3 to 13, 3 to 14, 3 to 15, 3 to 16, 3 to 17, 3 to 18, 3 to19, 3 to 20, 3 to 25, 3 to 30, 3 to 35, 3 to 40, 3 to 45, 3 to 50, 3 to55, 3 to 60, 3 to 65, 3 to 70, 3 to 75, 3 to 80, 3 to 85, 3 to 90, 3 to95, 3 to 100 percent surface modifications.

In some embodiments the concentration of surface modifications is in therange of 4 to 5, 4 to 6, 4 to 7, 4 to 8, 4 to 9, 4 to 10, 4 to 11, 4 to12, 4 to 13, 4 to 14, 4 to 15, 4 to 16, 4 to 17, 4 to 18, 4 to 19, 4 to20, 4 to 25, 4 to 30, 4 to 35, 4 to 40, 4 to 45, 4 to 50, 4 to 55, 4 to60, 4 to 65, 4 to 70, 4 to 75, 4 to 80, 4 to 85, 4 to 90, 4 to 95, 4 to100 percent surface modifications.

In some embodiments the concentration of surface modifications is in therange of 5 to 6, 5 to 7, 5 to 8, 5 to 9, 5 to 10, 5 to 11, 5 to 12, 5 to13, 5 to 14, 5 to 15, 5 to 16, 5 to 17, 5 to 18, 5 to 19, 5 to 20, 5 to25, 5 to 30, 5 to 35, 5 to 40, 5 to 45, 5 to 50, 5 to 55, 5 to 60, 5 to65, 5 to 70, 5 to 75, 5 to 80, 5 to 85, 5 to 90, 5 to 95, 5 to 100percent surface modifications.

In some embodiments the concentration of surface modifications is in therange of 6 to 7, 6 to 8, 6 to 9, 6 to 10, 6 to 11, 6 to 12, 6 to 13, 6to 14, 6 to 15, 6 to 16, 6 to 17, 6 to 18, 6 to 19, 6 to 20, 6 to 25, 6to 30, 6 to 35, 6 to 40, 6 to 45, 6 to 50, 6 to 55, 6 to 60, 6 to 65, 6to 70, 6 to 75, 6 to 80, 6 to 85, 6 to 90, 6 to 95, 6 to 100 percentsurface modifications.

In some embodiments the concentration of surface modifications is in therange of 7 to 8, 7 to 9, 7 to 10, 7 to 11, 7 to 12, 7 to 13, 7 to 14, 7to 15, 7 to 16, 7 to 17, 7 to 18, 7 to 19, 7 to 20, 7 to 25, 7 to 30, 7to 35, 7 to 40, 7 to 45, 7 to 50, 7 to 55, 7 to 60, 7 to 65, 7 to 70, 7to 75, 7 to 80, 7 to 85, 7 to 90, 7 to 95, 7 to 100 percent surfacemodifications.

In some embodiments the concentration of surface modifications is in therange of 8 to 9, 8 to 10, 8 to 11, 8 to 12, 8 to 13, 8 to 14, 8 to 15, 8to 16, 8 to 17, 8 to 18, 8 to 19, 8 to 20, 8 to 25, 8 to 30, 8 to 35, 8to 40, 8 to 45, 8 to 50, 8 to 55, 8 to 60, 8 to 65, 8 to 70, 8 to 75, 8to 80, 8 to 85, 8 to 90, 8 to 95, 8 to 100 percent surfacemodifications.

In some embodiments the concentration of surface modifications is in therange of 9 to 10, 9 to 11, 9 to 12, 9 to 13, 9 to 14, 9 to 15, 9 to 16,9 to 17, 9 to 18, 9 to 19, 9 to 20, 9 to 25, 9 to 30, 9 to 35, 9 to 40,9 to 45, 9 to 50, 9 to 55, 9 to 60, 9 to 65, 9 to 70, 9 to 75, 9 to 80,9 to 85, 9 to 90, 9 to 95, 9 to 100 percent surface modifications.

In some embodiments the concentration of surface modifications is in therange of 10 to 11, 10 to 12, 10 to 13, 10 to 14, 10 to 15, 10 to 16, 10to 17, 10 to 18, 10 to 19, to 20, 10 to 25, 10 to 30, 10 to 35, 10 to40, 10 to 45, 10 to 50, 10 to 55, 10 to 60, 10 to 65, 10 to 70, 10 to75, 10 to 80, 10 to 85, 10 to 90, 10 to 95, 10 to 100 percent surfacemodifications. In some embodiments, the concentration of surfacemodifications is in the range of 10 to 100 percent surfacemodifications.

In some embodiments the concentration of surface modifications is in therange of 20 to 25, 20 to 30, 20 to 35, 20 to 40, 20 to 45, 20 to 50, 20to 55, 20 to 60, 20 to 65, to 70, 20 to 75, 20 to 80, 20 to 85, 20 to90, 20 to 95, 20 to 100 percent surface modifications.

In some embodiments the concentration of surface modifications is in therange of 30 to 35, 30 to 40, 30 to 45, 30 to 50, 30 to 55, 30 to 60, 30to 65, 30 to 70, 30 to 75, to 80, 30 to 85, 30 to 90, 30 to 95, 30 to100 percent surface modifications.

In some embodiments the concentration of surface modifications is in therange of 40 to 45, 40 to 50, 40 to 55, 40 to 60, 40 to 65, 40 to 70, 40to 75, 40 to 80, 40 to 85, to 90, 40 to 95, 40 to 100 percent surfacemodifications.

In some embodiments the concentration of surface modifications is in therange of 50 to 55, 50 to 60, 50 to 65, 50 to 70, 50 to 75, 50 to 80, 50to 85, 50 to 90, 50 to 95, 50 to 100 percent surface modifications.

In some embodiments the concentration of surface modifications is in therange of 60 to 65, 60 to 70, 60 to 75, 60 to 80, 60 to 85, 60 to 90, 60to 95, 60 to 100 percent surface modifications.

In some embodiments the concentration of surface modifications is in therange of 70 to 75, 70 to 80, 70 to 85, 70 to 90, 70 to 95, 70 to 100percent surface modifications.

In some embodiments the concentration of surface modifications is in therange of 80 to 85, 80 to 90, 80 to 95, 80 to 100 percent surfacemodifications.

In some embodiments the concentration of surface modifications is in therange of 90 to 95, 90 to 100 percent surface modifications.

In some embodiments, the capsule or product is provided as a preparationand at least 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95% or 100% of the capsules or products in the preparation have aconcentration of attached compounds described herein.

In some embodiments, the hydrogel capsules have a mean diameter that isgreater than 1 mm and less than 8 mm, greater than 1.5 mm and less than8 mm, greater than 2 mm and less than 8 mm, greater than 2.5 mm and lessthan 8 mm, greater than 3 mm and less than 8 mm, greater than 3.5 mm andless than 8 mm, greater than 4 mm and less than 8 mm, greater than 4.5mm and less than 8 mm, greater than 5 mm and less than 8 mm, greaterthan 5.5 mm and less than 8 mm, greater than 6 mm and less than 8 mm,greater than 6.5 mm and less than 8 mm, greater than 7 mm and less than8 mm, or greater than 7.5 mm and less than 8 mm, and, independently,pores in a size range of 0.1 μm to 10 μm, 0.1 μm to 9 μm, 0.1 μm to 8μm, 0.1 μm to 7 μm, 0.1 μm to 6 μm, 0.1 μm to 5 μm, 0.1 μm to 4 μm, 0.1μm to 3 μm, 0.1 μm to 2 μm, 0.15 μm to 10 μm, 0.15 μm to 9 μm, 0.15 μmto 8 μm, 0.15 μm to 7 μm, 0.15 μm to 6 μm, 0.15 μm to 5 μm, 0.15 μm to 4μm, 0.15 μm to 3 μm, 0.15 μm to 2 μm, 0.2 μm to 10 μm, 0.2 μm to 9 μm,0.2 μm to 8 μm, 0.2 μm to 7 μm, 0.2 μm to 6 μm, 0.2 μm to 5 μm, 0.2 μmto 4 μm, 0.2 μm to 3 μm, 0.25 μm to 10 μm, 0.25 μm to 9 μm, 0.25 μm to 8μm, 0.25 μm to 7 μm, 0.25 μm to 6 μm, 0.25 μm to 5 μm, 0.25 μm to 4 μm,0.25 μm to 3 μm, 0.3 μm to 10 μm, 0.3 μm to 9 μm, 0.3 μm to 8 μm, 0.3 μmto 7 μm, 0.3 μm to 6 μm, 0.3 μm to 5 μm, 0.3 μm to 4 μm, 0.35 μm to 10μm, 0.35 μm to 9 μm, 0.35 μm to 8 μm, 0.35 μm to 7 μm, 0.35 μm to 6 μm,0.35 μm to 5 μm, 0.35 μm to 4 μm, 0.4 μm to 10 μm, 0.4 μm to 9 μm, 0.4μm to 8 μm, 0.4 μm to 7 μm, 0.4 μm to 6 μm, 0.4 μm to 5 μm, 0.45 μm to10 μm, 0.45 μm to 9 μm, 0.45 μm to 8 μm, 0.45 μm to 7 μm, 0.45 μm to 6μm, 0.45 μm to 5 μm, 0.5 μm to μm, 0.5 μm to 9 μm, 0.5 μm to 8 μm, 0.5μm to 7 μm, 0.5 μm to 6 μm, 0.55 μm to 10 μm, 0.55 μm to 9 μm, 0.55 μmto 8 μm, 0.55 μm to 7 μm, 0.55 μm to 6 μm, 0.6 μm to μm, 0.6 μm to 9 μm,0.6 μm to 8 μm, 0.6 μm to 7 μm, 0.65 μm to 10 μm, 0.65 μm to 9 μm, 0.65μm to 8 μm, 0.65 μm to 7 μm, 0.7 μm to 10 μm, 0.7 μm to 9 μm, 0.7 μm to8 μm, 0.75 μm to 10 μm, 0.75 μm to 9 μm, 0.75 μm to 8 μm, 0.8 μm to 10μm, 0.8 μm to 9 μm, 0.85 μm to 10 μm, 0.85 μm to 9 μm, 0.9 μm to 10 μm,0.95 μm to 10 μm, 1 μm to μm, 1 μm to 10 μm, 1 μm to 9 μm, 1 μm to 8 μm,1 μm to 7 μm, 1 μm to 6 μm, 1 μm to 5 μm, 1 μm to 4 μm, 1 μm to 3 μm, 1μm to 2 μm, 1.5 μm to 10 μm, 1.5 μm to 9 μm, 1.5 μm to 8 μm, 1.5 μm to 7μm, 1.5 μm to 6 μm, 1.5 μm to 5 μm, 1.5 μm to 4 μm, 1.5 μm to 3 μm, 1.5μm to 2 μm, 2 μm to 10 μm, 2 μm to 9 μm, 2 μm to 8 μm, 2 μm to 7 μm, 2μm to 6 μm, 2 μm to 5 μm, 2 μm to 4 μm, 2 μm to 3 μm, 2.5 μm to 10 μm,2.5 μm to 9 μm, 2.5 μm to 8 μm, 2.5 μm to 7 μm, 2.5 μm to 6 μm, 2.5 μmto 5 μm, 2.5 μm to 4 μm, 2.5 μm to 3 μm, 3 μm to 10 μm, 3 μm to 9 μm, 3μm to 8 μm, 3 μm to 7 μm, 3 μm to 6 μm, 3 μm to 5 μm, 3 μm to 4 μm, 3.5μm to 10 μm, 3.5 μm to 9 μm, 3.5 μm to 8 μm, 3.5 μm to 7 μm, 3.5 μm to 6μm, 3.5 μm to 5 μm, 3.5 μm to 4 μm, 4 μm to 10 μm, 4 μm to 9 μm, 4 μm to8 μm, 4 μm to 7 μm, 4 μm to 6 μm, 4 μm to 5 μm, 4.5 μm to 10 μm, 4.5 μmto 9 μm, 4.5 μm to 8 μm, 4.5 μm to 7 μm, 4.5 μm to 6 μm, 4.5 μm to 5 μm,μm to 10 μm, 5 μm to 9 μm, 5 μm to 8 μm, 5 μm to 7 μm, 5 μm to 6 μm, 5.5μm to 10 μm, 5.5 μm to 9 μm, 5.5 μm to 8 μm, 5.5 μm to 7 μm, 5.5 μm to 6μm, 6 μm to 10 μm, 6 μm to 9 μm, 6 μm to 8 μm, 6 μm to 7 μm, 6.5 μm to10 μm, 6.5 μm to 9 μm, 6.5 μm to 8 μm, 6.5 μm to 7 μm, 7 μm to 10 μm, 7μm to 9 μm, 7 μm to 8 μm, 7.5 μm to 10 μm, 7.5 μm to 9 μm, 7.5 μm to 8μm, 8 μm to 10 μm, 8 μm to 9 μm, 8.5 μm to 10 μm, 8.5 μm to 9 μm, 9 μmto 10 μm, or 9.5 μm to 10 μm.

In some embodiments, the hydrogel capsule is provided as a preparationand at least 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95% or 100% of the hydrogel capsules in the preparation have acombination of diameter and pore size described herein.

In some embodiments, the hydrogel capsules have a mean diameter that isgreater than 1 mm and less than 8 mm, greater than 1.5 mm and less than8 mm, greater than 2 mm and less than 8 mm, greater than 2.5 mm and lessthan 8 mm, greater than 3 mm and less than 8 mm, greater than 3.5 mm andless than 8 mm, greater than 4 mm and less than 8 mm, greater than 4.5mm and less than 8 mm, greater than 5 mm and less than 8 mm, greaterthan 5.5 mm and less than 8 mm, greater than 6 mm and less than 8 mm,greater than 6.5 mm and less than 8 mm, greater than 7 mm and less than8 mm, or greater than 7.5 mm and less than 8 mm, and, independently, thedensity is at least 0.1, 0.2, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65,70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180,190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 320, 340,360, 380, 400, 420, 440, 460, 480, 500, 550, 600, 650, 700, 750, 800,850, 900, or 1000 chemical modifications per μm² on the surface of thehydrogel capsules, in the interior of the hydrogel capsules, or both.

In some embodiments, the hydrogel capsules have a mean diameter or sizein a range of 1 mm to 8 mm, 1 mm to 6 mm, 1 mm to 5 mm, 1 mm to 4 mm, 1mm to 3 mm, 1 mm to 2 mm, 1 mm to 1.5 mm, 1.5 mm to 8 mm, 1.5 mm to 6mm, 1.5 mm to 5 mm, 1.5 mm to 4 mm, 1.5 mm to 3 mm, 1.5 mm to 2 mm, 2 mmto 8 mm, 2 mm to 7 mm, 2 mm to 6 mm, 2 mm to 5 mm, 2 mm to 4 mm, 2 mm to3 mm, 2.5 mm to 8 mm, 2.5 mm to 7 mm, 2.5 mm to 6 mm, 2.5 mm to 5 mm,2.5 mm to 4 mm, 2.5 mm to 3 mm, 3 mm to 8 mm, 3 mm to 7 mm, 3 mm to 6mm, 3 mm to 5 mm, 3 mm to 4 mm, 3.5 mm to 8 mm, 3.5 mm to 7 mm, 3.5 mmto 6 mm, 3.5 mm to 5 mm, 3.5 mm to 4 mm, 4 mm to 8 mm, 4 mm to 7 mm, 4mm to 6 mm, 4 mm to 5 mm, 4.5 mm to 8 mm, 4.5 mm to 7 mm, 4.5 mm to 6mm, 4.5 mm to 5 mm, 5 mm to 8 mm, 5 mm to 7 mm, 5 mm to 6 mm, 5.5 mm to8 mm, 5.5 mm to 7 mm, 5.5 mm to 6 mm, 6 mm to 8 mm, 6 mm to 7 mm, 6.5 mmto 8 mm, 6.5 mm to 7 mm, 7 mm to 8 mm, or 7.5 mm to 8 mm, and a densityin the range of 0.1 to 0.2, 0.1 to 0.5, 0.1 to 1, 0.1 to 2, 0.1 to 3,0.1 to 4, 0.1 to 5, 0.1 to 6, 0.1 to 7, 0.1 to 8, 0.1 to 9, 0.1 to 10,0.1 to 11, 0.1 to 12, 0.1 to 13, 0.1 to 14, 0.1 to 15, 0.1 to 16, 0.1 to17, 0.1 to 18, 0.1 to 19, 0.1 to 20, 0.1 to 25, 0.1 to 30, 0.1 to 35,0.1 to 40, 0.1 to 45, 0.1 to 50, 0.1 to 55, 0.1 to 60, 0.1 to 65, 0.1 to70, 0.1 to 75, 0.1 to 80, 0.1 to 85, 0.1 to 90, 0.1 to 95, 0.1 to 100,0.1 to 110, 0.1 to 120, 0.1 to 130, 0.1 to 140, 0.1 to 150, 0.1 to 160,0.1 to 170, 0.1 to 180, 0.1 to 190, 0.1 to 200, 0.1 to 210, 0.1 to 220,0.1 to 230, 0.1 to 240, 0.1 to 250, 0.1 to 260, 0.1 to 270, 0.1 to 280,0.1 to 290, 0.1 to 300, 0.1 to 320, 0.1 to 340, 0.1 to 360, 0.1 to 380,0.1 to 400, 0.1 to 420, 0.1 to 440, 0.1 to 460, 0.1 to 480, 0.1 to 500,0.1 to 550, 0.1 to 600, 0.1 to 650, 0.1 to 700, 0.1 to 750, 0.1 to 800,0.1 to 850, 0.1 to 900, 0.1 to 1000, 0.2 to 0.5, 0.0 to 1, 0.2 to 2, 0.2to 3, 0.2 to 4, 0.2 to 5, 0.2 to 6, 0.2 to 7, 0.2 to 8, 0.2 to 9, 0.2 to10, 0.2 to 11, 0.2 to 12, 0.2 to 13, 0.2 to 14, 0.2 to 15, 0.2 to 16,0.2 to 17, 0.2 to 18, 0.2 to 19, 0.2 to 20, 0.2 to 25, 0.2 to 30, 0.2 to35, 0.2 to 40, 0.2 to 45, 0.2 to 50, 0.2 to 55, 0.2 to 60, 0.2 to 65,0.2 to 70, 0.2 to 75, 0.2 to 80, 0.2 to 85, 0.2 to 90, 0.2 to 95, 0.2 to100, 0.2 to 110, 0.2 to 120, 0.2 to 130, 0.2 to 140, 0.2 to 150, 0.2 to160, 0.2 to 170, 0.2 to 180, 0.2 to 190, 0.2 to 200, 0.2 to 210, 0.2 to220, 0.2 to 230, 0.2 to 240, 0.2 to 250, 0.2 to 260, 0.2 to 270, 0.2 to280, 0.2 to 290, 0.2 to 300, 0.2 to 320, 0.2 to 340, 0.2 to 360, 0.2 to380, 0.2 to 400, 0.2 to 420, 0.2 to 440, 0.2 to 460, 0.2 to 480, 0.2 to500, 0.2 to 550, 0.2 to 600, 0.2 to 650, 0.2 to 700, 0.2 to 750, 0.2 to800, 0.2 to 850, 0.2 to 900, 0.2 to 1000, 0.5 to 1, 0.5 to 2, 0.5 to 3,0.5 to 4, 0.5 to 5, 0.5 to 6, 0.5 to 7, 0.5 to 8, 0.5 to 9, 0.5 to 10,0.5 to 11, 0.5 to 12, 0.5 to 13, 0.5 to 14, 0.5 to 15, 0.5 to 16, 0.5 to17, 0.5 to 18, 0.5 to 19, 0.5 to 20, 0.5 to 25, 0.5 to 30, 0.5 to 35,0.5 to 40, 0.5 to 45, 0.5 to 50, 0.5 to 55, 0.5 to 60, 0.5 to 65, 0.5 to70, 0.5 to 75, 0.5 to 80, 0.5 to 85, 0.5 to 90, 0.5 to 95, 0.5 to 100,0.5 to 110, 0.5 to 120, 0.5 to 130, 0.5 to 140, 0.5 to 150, 0.5 to 160,0.5 to 170, 0.5 to 180, 0.5 to 190, 0.5 to 200, 0.5 to 210, 0.5 to 220,0.5 to 230, 0.5 to 240, 0.5 to 250, 0.5 to 260, 0.5 to 270, 0.5 to 280,0.5 to 290, 0.5 to 300, 0.5 to 320, 0.5 to 340, 0.5 to 360, 0.5 to 380,0.5 to 400, 0.5 to 420, 0.5 to 440, 0.5 to 460, 0.5 to 480, 0.5 to 500,0.5 to 550, 0.5 to 600, 0.5 to 650, 0.5 to 700, 0.5 to 750, 0.5 to 800,0.5 to 850, 0.5 to 900, 0.5 to 1000, 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 1 to 11, 1 to 12, 1 to 13, 1 to14, 1 to 15, 1 to 16, 1 to 17, 1 to 18, 1 to 19, 1 to 20, 1 to 25, 1 to30, 1 to 35, 1 to 40, 1 to 45, 1 to 50, 1 to 55, 1 to 60, 1 to 65, 1 to70, 1 to 75, 1 to 80, 1 to 85, 1 to 90, 1 to 95, 1 to 100, 1 to 110, 1to 120, 1 to 130, 1 to 140, 1 to 150, 1 to 160, 1 to 170, 1 to 180, 1 to190, 1 to 200, 1 to 210, 1 to 220, 1 to 230, 1 to 240, 1 to 250, 1 to260, 1 to 270, 1 to 280, 1 to 290, 1 to 300, 1 to 320, 1 to 340, 1 to360, 1 to 380, 1 to 400, 1 to 420, 1 to 440, 1 to 460, 1 to 480, 1 to500, 1 to 550, 1 to 600, 1 to 650, 1 to 700, 1 to 750, 1 to 800, 1 to850, 1 to 900, 1 to 1000, 2 to 3, 2 to 4, 2 to 5, 2 to 6, 2 to 7, 2 to8, 2 to 9, 2 to 10, 2 to 11, 2 to 12, 2 to 13, 2 to 14, 2 to 15, 2 to16, 2 to 17, 2 to 18, 2 to 19, 2 to 20, 2 to 25, 2 to 30, 2 to 35, 2 to40, 2 to 45, 2 to 50, 2 to 55, 2 to 60, 2 to 65, 2 to 70, 2 to 75, 2 to80, 2 to 85, 2 to 90, 2 to 95, 2 to 100, 2 to 110, 2 to 120, 2 to 130, 2to 140, 2 to 150, 2 to 160, 2 to 170, 2 to 180, 2 to 190, 2 to 200, 2 to210, 2 to 220, 2 to 230, 2 to 240, 2 to 250, 2 to 260, 2 to 270, 2 to280, 2 to 290, 2 to 300, 2 to 320, 2 to 340, 2 to 360, 2 to 380, 2 to400, 2 to 420, 2 to 440, 2 to 460, 2 to 480, 2 to 500, 2 to 550, 2 to600, 2 to 650, 2 to 700, 2 to 750, 2 to 800, 2 to 850, 2 to 900, 2 to1000, 3 to 4, 3 to 5, 3 to 6, 3 to 7, 3 to 8, 3 to 9, 3 to 10, 3 to 11,3 to 12, 3 to 13, 3 to 14, 3 to 15, 3 to 16, 3 to 17, 3 to 18, 3 to 19,3 to 20, 3 to 25, 3 to 30, 3 to 35, 3 to 40, 3 to 45, 3 to 50, 3 to 55,3 to 60, 3 to 65, 3 to 70, 3 to 75, 3 to 80, 3 to 85, 3 to 90, 3 to 95,3 to 100, 3 to 110, 3 to 120, 3 to 130, 3 to 140, 3 to 150, 3 to 160, 3to 170, 3 to 180, 3 to 190, 3 to 200, 3 to 210, 3 to 220, 3 to 230, 3 to240, 3 to 250, 3 to 260, 3 to 270, 3 to 280, 3 to 290, 3 to 300, 3 to320, 3 to 340, 3 to 360, 3 to 380, 3 to 400, 3 to 420, 3 to 440, 3 to460, 3 to 480, 3 to 500, 3 to 550, 3 to 600, 3 to 650, 3 to 700, 3 to750, 3 to 800, 3 to 850, 3 to 900, 3 to 1000, 4 to 5, 4 to 6, 4 to 7, 4to 8, 4 to 9, 4 to 10, 4 to 11, 4 to 12, 4 to 13, 4 to 14, 4 to 15, 4 to16, 4 to 17, 4 to 18, 4 to 19, 4 to 20, 4 to 25, 4 to 30, 4 to 35, 4 to40, 4 to 45, 4 to 50, 4 to 55, 4 to 60, 4 to 65, 4 to 70, 4 to 75, 4 to80, 4 to 85, 4 to 90, 4 to 95, 4 to 100, 4 to 110, 4 to 120, 4 to 130, 4to 140, 4 to 150, 4 to 160, 4 to 170, 4 to 180, 4 to 190, 4 to 200, 4 to210, 4 to 220, 4 to 230, 4 to 240, 4 to 250, 4 to 260, 4 to 270, 4 to280, 4 to 290, 4 to 300, 4 to 320, 4 to 340, 4 to 360, 4 to 380, 4 to400, 4 to 420, 4 to 440, 4 to 460, 4 to 480, 4 to 500, 4 to 550, 4 to600, 4 to 650, 4 to 700, 4 to 750, 4 to 800, 4 to 850, 4 to 900, 4 to1000, 5 to 6, 5 to 7, 5 to 8, 5 to 9, 5 to 10, 5 to 11, 5 to 12, 5 to13, 5 to 14, 5 to 15, 5 to 16, 5 to 17, 5 to 18, 5 to 19, 5 to 20, 5 to25, 5 to 30, 5 to 35, 5 to 40, 5 to 45, 5 to 50, 5 to 55, 5 to 60, 5 to65, 5 to 70, 5 to 75, 5 to 80, 5 to 85, 5 to 90, 5 to 95, 5 to 100, 5 to110, 5 to 120, 5 to 130, 5 to 140, 5 to 150, 5 to 160, 5 to 170, 5 to180, 5 to 190, 5 to 200, 5 to 210, 5 to 220, 5 to 230, 5 to 240, 5 to250, 5 to 260, 5 to 270, 5 to 280, 5 to 290, to 300, 5 to 320, 5 to 340,5 to 360, 5 to 380, 5 to 400, 5 to 420, 5 to 440, 5 to 460, 5 to 480, 5to 500, 5 to 550, 5 to 600, 5 to 650, 5 to 700, 5 to 750, 5 to 800, 5 to850, 5 to 900, to 1000, 6 to 7, 6 to 8, 6 to 9, 6 to 10, 6 to 11, 6 to12, 6 to 13, 6 to 14, 6 to 15, 6 to 16, 6 to 17, 6 to 18, 6 to 19, 6 to20, 6 to 25, 6 to 30, 6 to 35, 6 to 40, 6 to 45, 6 to 50, 6 to 55, 6 to60, 6 to 65, 6 to 70, 6 to 75, 6 to 80, 6 to 85, 6 to 90, 6 to 95, 6 to100, 6 to 110, 6 to 120, 6 to 130, 6 to 140, 6 to 150, 6 to 160, 6 to170, 6 to 180, 6 to 190, 6 to 200, 6 to 210, 6 to 220, 6 to 230, 6 to240, 6 to 250, 6 to 260, 6 to 270, 6 to 280, 6 to 290, 6 to 300, 6 to320, 6 to 340, 6 to 360, 6 to 380, 6 to 400, 6 to 420, 6 to 440, 6 to460, 6 to 480, 6 to 500, 6 to 550, 6 to 600, 6 to 650, 6 to 700, 6 to750, 6 to 800, 6 to 850, 6 to 900, 6 to 1000, 7 to 8, 7 to 9, 7 to 10, 7to 11, 7 to 12, 7 to 13, 7 to 14, 7 to 15, 7 to 16, 7 to 17, 7 to 18, 7to 19, 7 to 20, 7 to 25, 7 to 30, 7 to 35, 7 to 40, 7 to 45, 7 to 50, 7to 55, 7 to 60, 7 to 65, 7 to 70, 7 to 75, 7 to 80, 7 to 85, 7 to 90, 7to 95, 7 to 100, 7 to 110, 7 to 120, 7 to 130, 7 to 140, 7 to 150, 7 to160, 7 to 170, 7 to 180, 7 to 190, 7 to 200, 7 to 210, 7 to 220, 7 to230, 7 to 240, 7 to 250, 7 to 260, 7 to 270, 7 to 280, 7 to 290, 7 to300, 7 to 320, 7 to 340, 7 to 360, 7 to 380, 7 to 400, 7 to 420, 7 to440, 7 to 460, 7 to 480, 7 to 500, 7 to 550, 7 to 600, 7 to 650, 7 to700, 7 to 750, 7 to 800, 7 to 850, 7 to 900, 7 to 1000, 8 to 9, 8 to 10,8 to 11, 8 to 12, 8 to 13, 8 to 14, 8 to 15, 8 to 16, 8 to 17, 8 to 18,8 to 19, 8 to 20, 8 to 25, 8 to 30, 8 to 35, 8 to 40, 8 to 45, 8 to 50,8 to 55, 8 to 60, 8 to 65, 8 to 70, 8 to 75, 8 to 80, 8 to 85, 8 to 90,8 to 95, 8 to 100, 8 to 110, 8 to 120, 8 to 130, 8 to 140, 8 to 150, 8to 160, 8 to 170, 8 to 180, 8 to 190, 8 to 200, 8 to 210, 8 to 220, 8 to230, 8 to 240, 8 to 250, 8 to 260, 8 to 270, 8 to 280, 8 to 290, 8 to300, 8 to 320, 8 to 340, 8 to 360, 8 to 380, 8 to 400, 8 to 420, 8 to440, 8 to 460, 8 to 480, 8 to 500, 8 to 550, 8 to 600, 8 to 650, 8 to700, 8 to 750, 8 to 800, 8 to 850, 8 to 900, 8 to 1000, 9 to 10, 9 to11, 9 to 12, 9 to 13, 9 to 14, 9 to 15, 9 to 16, 9 to 17, 9 to 18, 9 to19, 9 to 20, 9 to 25, 9 to 30, 9 to 35, 9 to 40, 9 to 45, 9 to 50, 9 to55, 9 to 60, 9 to 65, 9 to 70, 9 to 75, 9 to 80, 9 to 85, 9 to 90, 9 to95, 9 to 100, 9 to 110, 9 to 120, 9 to 130, 9 to 140, 9 to 150, 9 to160, 9 to 170, 9 to 180, 9 to 190, 9 to 200, 9 to 210, 9 to 220, 9 to230, 9 to 240, 9 to 250, 9 to 260, 9 to 270, 9 to 280, 9 to 290, 9 to300, 9 to 320, 9 to 340, 9 to 360, 9 to 380, 9 to 400, 9 to 420, 9 to440, 9 to 460, 9 to 480, 9 to 500, 9 to 550, 9 to 600, 9 to 650, 9 to700, 9 to 750, 9 to 800, 9 to 850, 9 to 900, 9 to 1000, 10 to 11, 10 to12, 10 to 13, 10 to 14, 10 to 15, 10 to 16, 10 to 17, 10 to 18, 10 to19, 10 to 20, 10 to 25, 10 to 30, 10 to 35, 10 to 40, 10 to 45, 10 to50, 10 to 55, 10 to 60, 10 to 65, 10 to 70, 10 to 75, 10 to 80, 10 to85, 10 to 90, 10 to 95, 10 to 100, 10 to 110, 10 to 120, 10 to 130, 10to 140, 10 to 150, 10 to 160, 10 to 170, 10 to 180, 10 to 190, 10 to200, 10 to 210, 10 to 220, 10 to 230, 10 to 240, 10 to 250, 10 to 260,10 to 270, 10 to 280, 10 to 290, 10 to 300, 10 to 320, 10 to 340, 10 to360, 10 to 380, 10 to 400, 10 to 420, 10 to 440, 10 to 460, 10 to 480,10 to 500, 10 to 550, 10 to 600, 10 to 650, 10 to 700, 10 to 750, 10 to800, 10 to 850, 10 to 900, 10 to 1000, 20 to 25, 20 to 30, to 35, 20 to40, 20 to 45, 20 to 50, 20 to 55, 20 to 60, 20 to 65, 20 to 70, 20 to75, 20 to 80, 20 to 85, 20 to 90, 20 to 95, 20 to 100, 20 to 110, 20 to120, 20 to 130, 20 to 140, to 150, 20 to 160, 20 to 170, 20 to 180, 20to 190, 20 to 200, 20 to 210, 20 to 220, 20 to 230, 20 to 240, 20 to250, 20 to 260, 20 to 270, 20 to 280, 20 to 290, 20 to 300, 20 to 320,20 to 340, 20 to 360, 20 to 380, 20 to 400, 20 to 420, 20 to 440, 20 to460, 20 to 480, 20 to 500, 20 to 550, 20 to 600, 20 to 650, 20 to 700,20 to 750, 20 to 800, 20 to 850, 20 to 900, 20 to 1000, 30 to 35, 30 to40, 30 to 45, 30 to 50, 30 to 55, 30 to 60, 30 to 65, 30 to 70, 30 to75, 30 to 80, 30 to 85, 30 to 90, 30 to 95, 30 to 100, 30 to 110, 30 to120, 30 to 130, 30 to 140, 30 to 150, 30 to 160, 30 to 170, 30 to 180,30 to 190, 30 to 200, 30 to 210, 30 to 220, 30 to 230, 30 to 240, 30 to250, 30 to 260, 30 to 270, 30 to 280, 30 to 290, 30 to 300, 30 to 320,30 to 340, 30 to 360, 30 to 380, 30 to 400, 30 to 420, 30 to 440, 30 to460, 30 to 480, 30 to 500, 30 to 550, 30 to 600, 30 to 650, 30 to 700,30 to 750, 30 to 800, 30 to 850, 30 to 900, 30 to 1000, 40 to 45, 40 to50, 40 to 55, to 60, 40 to 65, 40 to 70, 40 to 75, 40 to 80, 40 to 85,40 to 90, 40 to 95, 40 to 100, 40 to 110, 40 to 120, 40 to 130, 40 to140, 40 to 150, 40 to 160, 40 to 170, 40 to 180, 40 to 190, 40 to 200,40 to 210, 40 to 220, 40 to 230, 40 to 240, 40 to 250, 40 to 260, 40 to270, 40 to 280, 40 to 290, 40 to 300, 40 to 320, 40 to 340, 40 to 360,40 to 380, 40 to 400, 40 to 420, 40 to 440, 40 to 460, 40 to 480, 40 to500, 40 to 550, 40 to 600, 40 to 650, 40 to 700, 40 to 750, 40 to 800,40 to 850, 40 to 900, 40 to 1000, 50 to 55, 50 to 60, 50 to 65, 50 to70, 50 to 75, 50 to 80, 50 to 85, 50 to 90, 50 to 95, 50 to 100, 50 to110, 50 to 120, 50 to 130, 50 to 140, 50 to 150, 50 to 160, 50 to 170,50 to 180, 50 to 190, 50 to 200, 50 to 210, 50 to 220, 50 to 230, 50 to240, 50 to 250, 50 to 260, 50 to 270, 50 to 280, 50 to 290, 50 to 300,50 to 320, 50 to 340, 50 to 360, 50 to 380, 50 to 400, 50 to 420, 50 to440, 50 to 460, 50 to 480, 50 to 500, 50 to 550, 50 to 600, 50 to 650,50 to 700, 50 to 750, 50 to 800, 50 to 850, 50 to 900, 50 to 1000, 60 to65, 60 to 70, 60 to 75, 60 to 80, 60 to 85, 60 to 90, 60 to 95, 60 to100, 60 to 110, 60 to 120, 60 to 130, 60 to 140, 60 to 150, 60 to 160,60 to 170, 60 to 180, 60 to 190, 60 to 200, 60 to 210, 60 to 220, 60 to230, 60 to 240, 60 to 250, 60 to 260, 60 to 270, 60 to 280, 60 to 290,60 to 300, 60 to 320, 60 to 340, 60 to 360, 60 to 380, 60 to 400, 60 to420, 60 to 440, 60 to 460, 60 to 480, 60 to 500, 60 to 550, 60 to 600,60 to 650, 60 to 700, 60 to 750, 60 to 800, 60 to 850, 60 to 900, 60 to1000, 70 to 75, 70 to 80, 70 to 85, 70 to 90, 70 to 95, 70 to 100, 70 to110, 70 to 120, 70 to 130, 70 to 140, 70 to 150, 70 to 160, 70 to 170,70 to 180, 70 to 190, 70 to 200, 70 to 210, 70 to 220, 70 to 230, 70 to240, 70 to 250, 70 to 260, 70 to 270, 70 to 280, 70 to 290, 70 to 300,70 to 320, 70 to 340, 70 to 360, 70 to 380, 70 to 400, 70 to 420, 70 to440, 70 to 460, 70 to 480, 70 to 500, 70 to 550, 70 to 600, 70 to 650,70 to 700, 70 to 750, 70 to 800, 70 to 850, 70 to 900, 70 to 1000, 80 to85, 80 to 90, 80 to 95, 80 to 100, 80 to 110, 80 to 120, 80 to 130, 80to 140, 80 to 150, 80 to 160, 80 to 170, 80 to 180, 80 to 190, 80 to200, 80 to 210, 80 to 220, 80 to 230, 80 to 240, 80 to 250, 80 to 260,80 to 270, 80 to 280, 80 to 290, 80 to 300, 80 to 320, 80 to 340, 80 to360, 80 to 380, 80 to 400, 80 to 420, 80 to 440, 80 to 460, 80 to 480,80 to 500, 80 to 550, 80 to 600, 80 to 650, 80 to 700, 80 to 750, 80 to800, 80 to 850, 80 to 900, 80 to 1000, 90 to 95, 90 to 100, 90 to 110,90 to 120, 90 to 130, 90 to 140, 90 to 150, 90 to 160, 90 to 170, 90 to180, 90 to 190, 90 to 200, 90 to 210, 90 to 220, 90 to 230, 90 to 240,90 to 250, 90 to 260, 90 to 270, 90 to 280, 90 to 290, 90 to 300, 90 to320, 90 to 340, 90 to 360, 90 to 380, 90 to 400, 90 to 420, 90 to 440,90 to 460, 90 to 480, 90 to 500, 90 to 550, 90 to 600, 90 to 650, 90 to700, 90 to 750, 90 to 800, 90 to 850, 90 to 900, 90 to 1000, 100 to 110,100 to 120, 100 to 130, 100 to 140, 100 to 150, 100 to 160, 100 to 170,100 to 180, 100 to 190, 100 to 200, 100 to 210, 100 to 220, 100 to 230,100 to 240, 100 to 250, 100 to 260, 100 to 270, 100 to 280, 100 to 290,100 to 300, 100 to 320, 100 to 340, 100 to 360, 100 to 380, 100 to 400,100 to 420, 100 to 440, 100 to 460, 100 to 480, 100 to 500, 100 to 550,100 to 600, 100 to 650, 100 to 700, 100 to 750, 100 to 800, 100 to 850,100 to 900, 100 to 1000, 200 to 210, 200 to 220, 200 to 230, 200 to 240,200 to 250, 200 to 260, 200 to 270, 200 to 280, 200 to 290, 200 to 300,200 to 320, 200 to 340, 200 to 360, 200 to 380, 200 to 400, 200 to 420,200 to 440, 200 to 460, 200 to 480, 200 to 500, 200 to 550, 200 to 600,200 to 650, 200 to 700, 200 to 750, 200 to 800, 200 to 850, 200 to 900,200 to 1000, 300 to 320, 300 to 340, 300 to 360, 300 to 380, 300 to 400,300 to 420, 300 to 440, 300 to 460, 300 to 480, 300 to 500, 300 to 550,300 to 600, 300 to 650, 300 to 700, 300 to 750, 300 to 800, 300 to 850,300 to 900, 300 to 1000, 400 to 420, 400 to 440, 400 to 460, 400 to 480,400 to 500, 400 to 550, 400 to 600, 400 to 650, 400 to 700, 400 to 750,400 to 800, 400 to 850, 400 to 900, 400 to 1000, 500 to 550, 500 to 600,500 to 650, 500 to 700, 500 to 750, 500 to 800, 500 to 850, 500 to 900,500 to 1000, 600 to 650, 600 to 700, 600 to 750, 600 to 800, 600 to 850,600 to 900, 600 to 1000, 700 to 750, 700 to 800, 700 to 850, 700 to 900,700 to 1000, 800 to 850, 800 to 900, 800 to 1000, and 900 to 1000chemical derivatizations per μm² on the surface of the hydrogelcapsules, in the interior of the hydrogel capsules, or both

In some embodiments, the hydrogel capsule is provided as a preparationand at least 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95% or 100% of the hydrogel capsules in the preparation have acombination of hydrogel capsule size or diameter and derivatizationdensity described herein.

In some embodiments, the capsules or products have a mean diameter orsize that is greater than 1 mm and less than 8 mm, greater than 1.5 mmand less than 8 mm, greater than 2 mm and less than 8 mm, greater than2.5 mm and less than 8 mm, greater than 3 mm and less than 8 mm, greaterthan 3.5 mm and less than 8 mm, greater than 4 mm and less than 8 mm,greater than 4.5 mm and less than 8 mm, greater than 5 mm and less than8 mm, greater than 5.5 mm and less than 8 mm, greater than 6 mm and lessthan 8 mm, greater than 6.5 mm and less than 8 mm, greater than 7 mm andless than 8 mm, or greater than 7.5 mm and less than 8 mm, and,independently, the concentration of surface modifications is at least,is less than, or is 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30,35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, and 100 percent.

In some embodiments, the capsules or products have a mean diameter orsize in a range of 1 mm to 8 mm, 1 mm to 6 mm, 1 mm to 5 mm, 1 mm to 4mm, 1 mm to 3 mm, 1 mm to 2 mm, 1 mm to 1.5 mm, 1.5 mm to 8 mm, 1.5 mmto 6 mm, 1.5 mm to 5 mm, 1.5 mm to 4 mm, 1.5 mm to 3 mm, 1.5 mm to 2 mm,2 mm to 8 mm, 2 mm to 7 mm, 2 mm to 6 mm, 2 mm to 5 mm, 2 mm to 4 mm, 2mm to 3 mm, 2.5 mm to 8 mm, 2.5 mm to 7 mm, 2.5 mm to 6 mm, 2.5 mm to 5mm, 2.5 mm to 4 mm, 2.5 mm to 3 mm, 3 mm to 8 mm, 3 mm to 7 mm, 3 mm to6 mm, 3 mm to 5 mm, 3 mm to 4 mm, 3.5 mm to 8 mm, 3.5 mm to 7 mm, 3.5 mmto 6 mm, 3.5 mm to 5 mm, 3.5 mm to 4 mm, 4 mm to 8 mm, 4 mm to 7 mm, 4mm to 6 mm, 4 mm to 5 mm, 4.5 mm to 8 mm, 4.5 mm to 7 mm, 4.5 mm to 6mm, 4.5 mm to 5 mm, 5 mm to 8 mm, 5 mm to 7 mm, 5 mm to 6 mm, 5.5 mm to8 mm, 5.5 mm to 7 mm, 5.5 mm to 6 mm, 6 mm to 8 mm, 6 mm to 7 mm, 6.5 mmto 8 mm, 6.5 mm to 7 mm, 7 mm to 8 mm, or 7.5 mm to 8 mm, and aconcentration of surface modifications in the range of 0.1 to 0.2, 0.1to 0.5, 0.1 to 1, 0.1 to 2, 0.1 to 3, 0.1 to 4, 0.1 to 5, 0.1 to 6, 0.1to 7, 0.1 to 8, 0.1 to 9, 0.1 to 10, 0.1 to 11, 0.1 to 12, 0.1 to 13,0.1 to 14, 0.1 to 15, 0.1 to 16, 0.1 to 17, 0.1 to 18, 0.1 to 19, 0.1 to20, 0.1 to 25, 0.1 to 30, 0.1 to 35, 0.1 to 40, 0.1 to 45, 0.1 to 50,0.1 to 55, 0.1 to 60, 0.1 to 65, 0.1 to 70, 0.1 to 75, 0.1 to 80, 0.1 to85, 0.1 to 90, 0.1 to 95, 0.1 to 100, 0.2 to 0.5, 0.0 to 1, 0.2 to 2,0.2 to 3, 0.2 to 4, 0.2 to 5, 0.2 to 6, 0.2 to 7, 0.2 to 8, 0.2 to 9,0.2 to 10, 0.2 to 11, 0.2 to 12, 0.2 to 13, 0.2 to 14, 0.2 to 15, 0.2 to16, 0.2 to 17, 0.2 to 18, 0.2 to 19, 0.2 to 20, 0.2 to 25, 0.2 to 30,0.2 to 35, 0.2 to 40, 0.2 to 45, 0.2 to 50, 0.2 to 55, 0.2 to 60, 0.2 to65, 0.2 to 70, 0.2 to 75, 0.2 to 80, 0.2 to 85, 0.2 to 90, 0.2 to 95,0.2 to 100, 0.5 to 1, 0.5 to 2, 0.5 to 3, 0.5 to 4, 0.5 to 5, 0.5 to 6,0.5 to 7, 0.5 to 8, 0.5 to 9, 0.5 to 10, 0.5 to 11, 0.5 to 12, 0.5 to13, 0.5 to 14, 0.5 to 15, 0.5 to 16, 0.5 to 17, 0.5 to 18, 0.5 to 19,0.5 to 20, 0.5 to 25, 0.5 to 30, 0.5 to 35, 0.5 to 40, 0.5 to 45, 0.5 to50, 0.5 to 55, 0.5 to 60, 0.5 to 65, 0.5 to 70, 0.5 to 75, 0.5 to 80,0.5 to 85, 0.5 to 90, 0.5 to 95, 0.5 to 100, 1 to 2, 1 to 3, 1 to 4, 1to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 1 to 11, 1 to 12, 1 to13, 1 to 14, 1 to 15, 1 to 16, 1 to 17, 1 to 18, 1 to 19, 1 to 20, 1 to25, 1 to 30, 1 to 35, 1 to 40, 1 to 45, 1 to 50, 1 to 55, 1 to 60, 1 to65, 1 to 70, 1 to 75, 1 to 80, 1 to 85, 1 to 90, 1 to 95, 1 to 100, 2 to3, 2 to 4, 2 to 5, 2 to 6, 2 to 7, 2 to 8, 2 to 9, 2 to 10, 2 to 11, 2to 12, 2 to 13, 2 to 14, 2 to 15, 2 to 16, 2 to 17, 2 to 18, 2 to 19, 2to 20, 2 to 25, 2 to 30, 2 to 35, 2 to 40, 2 to 45, 2 to 50, 2 to 55, 2to 60, 2 to 65, 2 to 70, 2 to 75, 2 to 80, 2 to 85, 2 to 90, 2 to 95, 2to 100, 3 to 4, 3 to 5, 3 to 6, 3 to 7, 3 to 8, 3 to 9, 3 to 10, 3 to11, 3 to 12, 3 to 13, 3 to 14, 3 to 15, 3 to 16, 3 to 17, 3 to 18, 3 to19, 3 to 20, 3 to 25, 3 to 30, 3 to 35, 3 to 40, 3 to 45, 3 to 50, 3 to55, 3 to 60, 3 to 65, 3 to 70, 3 to 75, 3 to 80, 3 to 85, 3 to 90, 3 to95, 3 to 100, 4 to 5, 4 to 6, 4 to 7, 4 to 8, 4 to 9, 4 to 10, 4 to 11,4 to 12, 4 to 13, 4 to 14, 4 to 15, 4 to 16, 4 to 17, 4 to 18, 4 to 19,4 to 20, 4 to 25, 4 to 30, 4 to 35, 4 to 40, 4 to 45, 4 to 50, 4 to 55,4 to 60, 4 to 65, 4 to 70, 4 to 75, 4 to 80, 4 to 85, 4 to 90, 4 to 95,4 to 100, 5 to 6, 5 to 7, 5 to 8, 5 to 9, 5 to 10, 5 to 11, 5 to 12, 5to 13, 5 to 14, 5 to 15, 5 to 16, 5 to 17, 5 to 18, 5 to 19, 5 to 20, 5to 25, 5 to 30, 5 to 35, 5 to 40, 5 to 45, 5 to 50, 5 to 55, 5 to 60, 5to 65, 5 to 70, 5 to 75, 5 to 80, 5 to 85, 5 to 90, 5 to 95, 5 to 100, 6to 7, 6 to 8, 6 to 9, 6 to 10, 6 to 11, 6 to 12, 6 to 13, 6 to 14, 6 to15, 6 to 16, 6 to 17, 6 to 18, 6 to 19, 6 to 20, 6 to 25, 6 to 30, 6 to35, 6 to 40, 6 to 45, 6 to 50, 6 to 55, 6 to 60, 6 to 65, 6 to 70, 6 to75, 6 to 80, 6 to 85, 6 to 90, 6 to 95, 6 to 100, 7 to 8, 7 to 9, 7 to10, 7 to 11, 7 to 12, 7 to 13, 7 to 14, 7 to 15, 7 to 16, 7 to 17, 7 to18, 7 to 19, 7 to 20, 7 to 25, 7 to 30, 7 to 35, 7 to 40, 7 to 45, 7 to50, 7 to 55, 7 to 60, 7 to 65, 7 to 70, 7 to 75, 7 to 80, 7 to 85, 7 to90, 7 to 95, 7 to 100, 8 to 9, 8 to 10, 8 to 11, 8 to 12, 8 to 13, 8 to14, 8 to 15, 8 to 16, 8 to 17, 8 to 18, 8 to 19, 8 to 20, 8 to 25, 8 to30, 8 to 35, 8 to 40, 8 to 45, 8 to 50, 8 to 55, 8 to 60, 8 to 65, 8 to70, 8 to 75, 8 to 80, 8 to 85, 8 to 90, 8 to 95, 8 to 100, 9 to 10, 9 to11, 9 to 12, 9 to 13, 9 to 14, 9 to 15, 9 to 16, 9 to 17, 9 to 18, 9 to19, 9 to 20, 9 to 25, 9 to 30, 9 to 35, 9 to 40, 9 to 45, 9 to 50, 9 to55, 9 to 60, 9 to 65, 9 to 70, 9 to 75, 9 to 80, 9 to 85, 9 to 90, 9 to95, 9 to 100, 10 to 11, 10 to 12, 10 to 13, 10 to 14, 10 to 15, 10 to16, 10 to 17, 10 to 18, 10 to 19, 10 to 20, to 25, 10 to 30, 10 to 35,10 to 40, 10 to 45, 10 to 50, 10 to 55, 10 to 60, 10 to 65, 10 to 70, 10to 75, 10 to 80, 10 to 85, 10 to 90, 10 to 95, 10 to 100, 20 to 25, 20to 30, 20 to 35, 20 to 40, 20 to 45, 20 to 50, 20 to 55, 20 to 60, 20 to65, 20 to 70, 20 to 75, 20 to 80, to 85, 20 to 90, 20 to 95, 20 to 100,30 to 35, 30 to 40, 30 to 45, 30 to 50, 30 to 55, 30 to 60, 30 to 65, 30to 70, 30 to 75, 30 to 80, 30 to 85, 30 to 90, 30 to 95, 30 to 100, 40to 45, 40 to 50, 40 to 55, 40 to 60, 40 to 65, 40 to 70, 40 to 75, 40 to80, 40 to 85, 40 to 90, to 95, 40 to 100, 50 to 55, 50 to 60, 50 to 65,50 to 70, 50 to 75, 50 to 80, 50 to 85, 50 to 90, 50 to 95, 50 to 100,60 to 65, 60 to 70, 60 to 75, 60 to 80, 60 to 85, 60 to 90, 60 to 95, 60to 100, 70 to 75, 70 to 80, 70 to 85, 70 to 90, 70 to 95, 70 to 100, 80to 85, 80 to 90, 80 to 95, 80 to 100, 90 to 95, 90 to 100 percent.

In some embodiments, the capsule or product is provided as a preparationand at least 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95% or 100% of the capsules or products in the preparation have acombination of capsule or product size or diameter and concentrations ofsurface modifications described herein.

In some embodiments, the density of the chemical modifications is atleast, is less than, oris 0.1, 0.2, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60,65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180,190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 320, 340,360, 380, 400, 420, 440, 460, 480, 500, 550, 600, 650, 700, 750, 800,850, 900, or 1000 chemical modifications per μm² on the surface of thehydrogel capsules, in the interior of the hydrogel capsules, or both, orthe concentration of surface modifications is at least, is less than, oris 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50,55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 percent, and, independently,the hydrogel capsules have pores in a size range of 0.1 μm to 10 μm, 0.1μm to 9 μm, 0.1 μm to 8 μm, 0.1 μm to 7 μm, 0.1 μm to 6 μm, 0.1 μm to 5μm, 0.1 μm to 4 μm, 0.1 μm to 3 μm, 0.1 μm to 2 μm, 0.15 μm to 10 μm,0.15 μm to 9 μm, 0.15 μm to 8 μm, 0.15 μm to 7 μm, 0.15 μm to 6 μm, 0.15μm to 5 μm, 0.15 μm to 4 μm, 0.15 μm to 3 μm, 0.15 μm to 2 μm, 0.2 μm to10 μm, 0.2 μm to 9 μm, 0.2 μm to 8 μm, 0.2 μm to 7 μm, 0.2 μm to 6 μm,0.2 μm to 5 μm, 0.2 μm to 4 μm, 0.2 μm to 3 μm, 0.25 μm to 10 μm, 0.25μm to 9 μm, 0.25 μm to 8 μm, 0.25 μm to 7 μm, 0.25 μm to 6 μm, 0.25 μmto 5 μm, 0.25 μm to 4 μm, 0.25 μm to 3 μm, 0.3 μm to 10 μm, 0.3 μm to 9μm, 0.3 μm to 8 μm, 0.3 μm to 7 μm, 0.3 μm to 6 μm, 0.3 μm to 5 μm, 0.3μm to 4 μm, 0.35 μm to 10 μm, 0.35 μm to 9 μm, 0.35 μm to 8 μm, 0.35 μmto 7 μm, 0.35 μm to 6 μm, 0.35 μm to 5 μm, 0.35 μm to 4 μm, 0.4 μm to 10μm, 0.4 μm to 9 μm, 0.4 μm to 8 μm, 0.4 μm to 7 μm, 0.4 μm to 6 μm, 0.4μm to 5 μm, 0.45 μm to 10 μm, 0.45 μm to 9 μm, 0.45 μm to 8 μm, 0.45 μmto 7 μm, 0.45 μm to 6 μm, 0.45 μm to 5 μm, 0.5 μm to 10 μm, 0.5 μm to 9μm, 0.5 μm to 8 μm, 0.5 μm to 7 μm, 0.5 μm to 6 μm, 0.55 junto 10 μm,0.55 μm to 9 μm, 0.55 μm to 8 μm, 0.55 μm to 7 μm, 0.55 μm to 6 μm, 0.6μm to 10 μm, 0.6 μm to 9 μm, 0.6 μm to 8 μm, 0.6 μm to 7 μm, 0.65 μm to10 μm, 0.65 μm to 9 μm, 0.65 μm to 8 μm, 0.65 μm to 7 μm, 0.7 μm to 10μm, 0.7 μm to 9 μm, 0.7 μm to 8 μm, 0.75 μm to 10 μm, 0.75 μm to 9 μm,0.75 μm to 8 μm, 0.8 μm to 10 μm, 0.8 μm to 9 μm, 0.85 μm to 10 μm, 0.85μm to 9 μm, 0.9 μm to 10 μm, 0.95 μm to μm, 1 μm to 10 μm, 1 μm to 10μm, 1 μm to 9 μm, 1 μm to 8 μm, 1 μm to 7 μm, 1 junto 6 μm, 1 μm to 5μm, 1 μm to 4 μm, 1 μm to 3 μm, 1 μm to 2 μm, 1.5 μm to 10 μm, 1.5 μm to9 μm, 1.5 μm to 8 μm, 1.5 μm to 7 μm, 1.5 μm to 6 μm, 1.5 μm to 5 μm,1.5 μm to 4 μm, 1.5 μm to 3 μm, 1.5 μm to 2 μm, 2 μm to 10 μm, 2 μm to 9μm, 2 μm to 8 μm, 2 μm to 7 μm, 2 μm to 6 μm, 2 μm to 5 μm, 2 μm to 4μm, 2 μm to 3 μm, 2.5 μm to 10 μm, 2.5 μm to 9 μm, 2.5 μm to 8 μm, 2.5μm to 7 μm, 2.5 μm to 6 μm, 2.5 μm to 5 μm, 2.5 μm to 4 μm, 2.5 μm to 3μm, 3 μm to 10 μm, 3 μm to 9 μm, 3 μm to 8 μm, 3 μm to 7 μm, 3 μm to 6μm, 3 μm to 5 μm, 3 μm to 4 μm, 3.5 μm to 10 μm, 3.5 μm to 9 μm, 3.5 μmto 8 μm, 3.5 μm to 7 μm, 3.5 μm to 6 μm, 3.5 μm to 5 μm, 3.5 μm to 4 μm,4 μm to 10 μm, 4 μm to 9 μm, 4 μm to 8 μm, 4 μm to 7 μm, 4 μm to 6 μm, 4μm to 5 μm, 4.5 μm to 10 μm, 4.5 μm to 9 μm, 4.5 μm to 8 μm, 4.5 μm to 7μm, 4.5 μm to 6 μm, 4.5 μm to 5 μm, 5 μm to 10 μm, 5 μm to 9 μm, 5 μm to8 μm, 5 μm to 7 μm, 5 μm to 6 μm, 5.5 μm to 10 μm, 5.5 μm to 9 μm, 5.5μm to 8 μm, 5.5 μm to 7 μm, 5.5 μm to 6 μm, 6 μm to 10 μm, 6 μm to 9 μm,6 μm to 8 μm, 6 μm to 7 μm, 6.5 μm to 10 μm, 6.5 μm to 9 μm, 6.5 μm to 8μm, 6.5 μm to 7 μm, 7 μm to 10 μm, 7 μm to 9 μm, 7 μm to 8 μm, 7.5 μm to10 μm, 7.5 μm to 9 μm, 7.5 μm to 8 μm, 8 μm to 10 μm, 8 μm to 9 μm, 8.5μm to μm, 8.5 μm to 9 μm, 9 μm to 10 μm, or 9.5 μm to 10 μm.

In some embodiments, the density of the chemical derivatizations is inthe range of 0.1 to 0.2, 0.1 to 0.5, 0.1 to 1, 0.1 to 2, 0.1 to 3, 0.1to 4, 0.1 to 5, 0.1 to 6, 0.1 to 7, 0.1 to 8, 0.1 to 9, 0.1 to 10, 0.1to 11, 0.1 to 12, 0.1 to 13, 0.1 to 14, 0.1 to 15, 0.1 to 16, 0.1 to 17,0.1 to 18, 0.1 to 19, 0.1 to 20, 0.1 to 25, 0.1 to 30, 0.1 to 35, 0.1 to40, 0.1 to 45, 0.1 to 50, 0.1 to 55, 0.1 to 60, 0.1 to 65, 0.1 to 70,0.1 to 75, 0.1 to 80, 0.1 to 85, 0.1 to 90, 0.1 to 95, 0.1 to 100, 0.1to 110, 0.1 to 120, 0.1 to 130, 0.1 to 140, 0.1 to 150, 0.1 to 160, 0.1to 170, 0.1 to 180, 0.1 to 190, 0.1 to 200, 0.1 to 210, 0.1 to 220, 0.1to 230, 0.1 to 240, 0.1 to 250, 0.1 to 260, 0.1 to 270, 0.1 to 280, 0.1to 290, 0.1 to 300, 0.1 to 320, 0.1 to 340, 0.1 to 360, 0.1 to 380, 0.1to 400, 0.1 to 420, 0.1 to 440, 0.1 to 460, 0.1 to 480, 0.1 to 500, 0.1to 550, 0.1 to 600, 0.1 to 650, 0.1 to 700, 0.1 to 750, 0.1 to 800, 0.1to 850, 0.1 to 900, 0.1 to 1000, 0.2 to 0.5, 0.0 to 1, 0.2 to 2, 0.2 to3, 0.2 to 4, 0.2 to 5, 0.2 to 6, 0.2 to 7, 0.2 to 8, 0.2 to 9, 0.2 to10, 0.2 to 11, 0.2 to 12, 0.2 to 13, 0.2 to 14, 0.2 to 15, 0.2 to 16,0.2 to 17, 0.2 to 18, 0.2 to 19, 0.2 to 20, 0.2 to 25, 0.2 to 30, 0.2 to35, 0.2 to 40, 0.2 to 45, 0.2 to 50, 0.2 to 55, 0.2 to 60, 0.2 to 65,0.2 to 70, 0.2 to 75, 0.2 to 80, 0.2 to 85, 0.2 to 90, 0.2 to 95, 0.2 to100, 0.2 to 110, 0.2 to 120, 0.2 to 130, 0.2 to 140, 0.2 to 150, 0.2 to160, 0.2 to 170, 0.2 to 180, 0.2 to 190, 0.2 to 200, 0.2 to 210, 0.2 to220, 0.2 to 230, 0.2 to 240, 0.2 to 250, 0.2 to 260, 0.2 to 270, 0.2 to280, 0.2 to 290, 0.2 to 300, 0.2 to 320, 0.2 to 340, 0.2 to 360, 0.2 to380, 0.2 to 400, 0.2 to 420, 0.2 to 440, 0.2 to 460, 0.2 to 480, 0.2 to500, 0.2 to 550, 0.2 to 600, 0.2 to 650, 0.2 to 700, 0.2 to 750, 0.2 to800, 0.2 to 850, 0.2 to 900, 0.2 to 1000, 0.5 to 1, 0.5 to 2, 0.5 to 3,0.5 to 4, 0.5 to 5, 0.5 to 6, 0.5 to 7, 0.5 to 8, 0.5 to 9, 0.5 to 10,0.5 to 11, 0.5 to 12, 0.5 to 13, 0.5 to 14, 0.5 to 15, 0.5 to 16, 0.5 to17, 0.5 to 18, 0.5 to 19, 0.5 to 20, 0.5 to 25, 0.5 to 30, 0.5 to 35,0.5 to 40, 0.5 to 45, 0.5 to 50, 0.5 to 55, 0.5 to 60, 0.5 to 65, 0.5 to70, 0.5 to 75, 0.5 to 80, 0.5 to 85, 0.5 to 90, 0.5 to 95, 0.5 to 100,0.5 to 110, 0.5 to 120, 0.5 to 130, 0.5 to 140, 0.5 to 150, 0.5 to 160,0.5 to 170, 0.5 to 180, 0.5 to 190, 0.5 to 200, 0.5 to 210, 0.5 to 220,0.5 to 230, 0.5 to 240, 0.5 to 250, 0.5 to 260, 0.5 to 270, 0.5 to 280,0.5 to 290, 0.5 to 300, 0.5 to 320, 0.5 to 340, 0.5 to 360, 0.5 to 380,0.5 to 400, 0.5 to 420, 0.5 to 440, 0.5 to 460, 0.5 to 480, 0.5 to 500,0.5 to 550, 0.5 to 600, 0.5 to 650, 0.5 to 700, 0.5 to 750, 0.5 to 800,0.5 to 850, 0.5 to 900, 0.5 to 1000, 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 1 to 11, 1 to 12, 1 to 13, 1 to14, 1 to 15, 1 to 16, 1 to 17, 1 to 18, 1 to 19, 1 to 20, 1 to 25, 1 to30, 1 to 35, 1 to 40, 1 to 45, 1 to 50, 1 to 55, 1 to 60, 1 to 65, 1 to70, 1 to 75, 1 to 80, 1 to 85, 1 to 90, 1 to 95, 1 to 100, 1 to 110, 1to 120, 1 to 130, 1 to 140, 1 to 150, 1 to 160, 1 to 170, 1 to 180, 1 to190, 1 to 200, 1 to 210, 1 to 220, 1 to 230, 1 to 240, 1 to 250, 1 to260, 1 to 270, 1 to 280, 1 to 290, 1 to 300, 1 to 320, 1 to 340, 1 to360, 1 to 380, 1 to 400, 1 to 420, 1 to 440, 1 to 460, 1 to 480, 1 to500, 1 to 550, 1 to 600, 1 to 650, 1 to 700, 1 to 750, 1 to 800, 1 to850, 1 to 900, 1 to 1000, 2 to 3, 2 to 4, 2 to 5, 2 to 6, 2 to 7, 2 to8, 2 to 9, 2 to 10, 2 to 11, 2 to 12, 2 to 13, 2 to 14, 2 to 15, 2 to16, 2 to 17, 2 to 18, 2 to 19, 2 to 20, 2 to 25, 2 to 30, 2 to 35, 2 to40, 2 to 45, 2 to 50, 2 to 55, 2 to 60, 2 to 65, 2 to 70, 2 to 75, 2 to80, 2 to 85, 2 to 90, 2 to 95, 2 to 100, 2 to 110, 2 to 120, 2 to 130, 2to 140, 2 to 150, 2 to 160, 2 to 170, 2 to 180, 2 to 190, 2 to 200, 2 to210, 2 to 220, 2 to 230, 2 to 240, 2 to 250, 2 to 260, 2 to 270, 2 to280, 2 to 290, 2 to 300, 2 to 320, 2 to 340, 2 to 360, 2 to 380, 2 to400, 2 to 420, 2 to 440, 2 to 460, 2 to 480, 2 to 500, 2 to 550, 2 to600, 2 to 650, 2 to 700, 2 to 750, 2 to 800, 2 to 850, 2 to 900, 2 to1000, 3 to 4, 3 to 5, 3 to 6, 3 to 7, 3 to 8, 3 to 9, 3 to 10, 3 to 11,3 to 12, 3 to 13, 3 to 14, 3 to 15, 3 to 16, 3 to 17, 3 to 18, 3 to 19,3 to 20, 3 to 25, 3 to 30, 3 to 35, 3 to 40, 3 to 45, 3 to 50, 3 to 55,3 to 60, 3 to 65, 3 to 70, 3 to 75, 3 to 80, 3 to 85, 3 to 90, 3 to 95,3 to 100, 3 to 110, 3 to 120, 3 to 130, 3 to 140, 3 to 150, 3 to 160, 3to 170, 3 to 180, 3 to 190, 3 to 200, 3 to 210, 3 to 220, 3 to 230, 3 to240, 3 to 250, 3 to 260, 3 to 270, 3 to 280, 3 to 290, 3 to 300, 3 to320, 3 to 340, 3 to 360, 3 to 380, 3 to 400, 3 to 420, 3 to 440, 3 to460, 3 to 480, 3 to 500, 3 to 550, 3 to 600, 3 to 650, 3 to 700, 3 to750, 3 to 800, 3 to 850, 3 to 900, 3 to 1000, 4 to 5, 4 to 6, 4 to 7, 4to 8, 4 to 9, 4 to 10, 4 to 11, 4 to 12, 4 to 13, 4 to 14, 4 to 15, 4 to16, 4 to 17, 4 to 18, 4 to 19, 4 to 20, 4 to 25, 4 to 30, 4 to 35, 4 to40, 4 to 45, 4 to 50, 4 to 55, 4 to 60, 4 to 65, 4 to 70, 4 to 75, 4 to80, 4 to 85, 4 to 90, 4 to 95, 4 to 100, 4 to 110, 4 to 120, 4 to 130, 4to 140, 4 to 150, 4 to 160, 4 to 170, 4 to 180, 4 to 190, 4 to 200, 4 to210, 4 to 220, 4 to 230, 4 to 240, 4 to 250, 4 to 260, 4 to 270, 4 to280, 4 to 290, 4 to 300, 4 to 320, 4 to 340, 4 to 360, 4 to 380, 4 to400, 4 to 420, 4 to 440, 4 to 460, 4 to 480, 4 to 500, 4 to 550, 4 to600, 4 to 650, 4 to 700, 4 to 750, 4 to 800, 4 to 850, 4 to 900, 4 to1000, 5 to 6, 5 to 7, 5 to 8, 5 to 9, 5 to 10, 5 to 11, 5 to 12, 5 to13, 5 to 14, 5 to 15, 5 to 16, 5 to 17, 5 to 18, 5 to 19, 5 to 20, 5 to25, 5 to 30, 5 to 35, 5 to 40, 5 to 45, 5 to 50, 5 to 55, 5 to 60, 5 to65, 5 to 70, 5 to 75, 5 to 80, 5 to 85, 5 to 90, 5 to 95, 5 to 100, 5 to110, 5 to 120, 5 to 130, 5 to 140, 5 to 150, 5 to 160, 5 to 170, 5 to180, 5 to 190, 5 to 200, 5 to 210, 5 to 220, 5 to 230, 5 to 240, 5 to250, 5 to 260, 5 to 270, 5 to 280, 5 to 290, to 300, 5 to 320, 5 to 340,5 to 360, 5 to 380, 5 to 400, 5 to 420, 5 to 440, 5 to 460, 5 to 480, 5to 500, 5 to 550, 5 to 600, 5 to 650, 5 to 700, 5 to 750, 5 to 800, 5 to850, 5 to 900, to 1000, 6 to 7, 6 to 8, 6 to 9, 6 to 10, 6 to 11, 6 to12, 6 to 13, 6 to 14, 6 to 15, 6 to 16, 6 to 17, 6 to 18, 6 to 19, 6 to20, 6 to 25, 6 to 30, 6 to 35, 6 to 40, 6 to 45, 6 to 50, 6 to 55, 6 to60, 6 to 65, 6 to 70, 6 to 75, 6 to 80, 6 to 85, 6 to 90, 6 to 95, 6 to100, 6 to 110, 6 to 120, 6 to 130, 6 to 140, 6 to 150, 6 to 160, 6 to170, 6 to 180, 6 to 190, 6 to 200, 6 to 210, 6 to 220, 6 to 230, 6 to240, 6 to 250, 6 to 260, 6 to 270, 6 to 280, 6 to 290, 6 to 300, 6 to320, 6 to 340, 6 to 360, 6 to 380, 6 to 400, 6 to 420, 6 to 440, 6 to460, 6 to 480, 6 to 500, 6 to 550, 6 to 600, 6 to 650, 6 to 700, 6 to750, 6 to 800, 6 to 850, 6 to 900, 6 to 1000, 7 to 8, 7 to 9, 7 to 10, 7to 11, 7 to 12, 7 to 13, 7 to 14, 7 to 15, 7 to 16, 7 to 17, 7 to 18, 7to 19, 7 to 20, 7 to 25, 7 to 30, 7 to 35, 7 to 40, 7 to 45, 7 to 50, 7to 55, 7 to 60, 7 to 65, 7 to 70, 7 to 75, 7 to 80, 7 to 85, 7 to 90, 7to 95, 7 to 100, 7 to 110, 7 to 120, 7 to 130, 7 to 140, 7 to 150, 7 to160, 7 to 170, 7 to 180, 7 to 190, 7 to 200, 7 to 210, 7 to 220, 7 to230, 7 to 240, 7 to 250, 7 to 260, 7 to 270, 7 to 280, 7 to 290, 7 to300, 7 to 320, 7 to 340, 7 to 360, 7 to 380, 7 to 400, 7 to 420, 7 to440, 7 to 460, 7 to 480, 7 to 500, 7 to 550, 7 to 600, 7 to 650, 7 to700, 7 to 750, 7 to 800, 7 to 850, 7 to 900, 7 to 1000, 8 to 9, 8 to 10,8 to 11, 8 to 12, 8 to 13, 8 to 14, 8 to 15, 8 to 16, 8 to 17, 8 to 18,8 to 19, 8 to 20, 8 to 25, 8 to 30, 8 to 35, 8 to 40, 8 to 45, 8 to 50,8 to 55, 8 to 60, 8 to 65, 8 to 70, 8 to 75, 8 to 80, 8 to 85, 8 to 90,8 to 95, 8 to 100, 8 to 110, 8 to 120, 8 to 130, 8 to 140, 8 to 150, 8to 160, 8 to 170, 8 to 180, 8 to 190, 8 to 200, 8 to 210, 8 to 220, 8 to230, 8 to 240, 8 to 250, 8 to 260, 8 to 270, 8 to 280, 8 to 290, 8 to300, 8 to 320, 8 to 340, 8 to 360, 8 to 380, 8 to 400, 8 to 420, 8 to440, 8 to 460, 8 to 480, 8 to 500, 8 to 550, 8 to 600, 8 to 650, 8 to700, 8 to 750, 8 to 800, 8 to 850, 8 to 900, 8 to 1000, 9 to 10, 9 to11, 9 to 12, 9 to 13, 9 to 14, 9 to 15, 9 to 16, 9 to 17, 9 to 18, 9 to19, 9 to 20, 9 to 25, 9 to 30, 9 to 35, 9 to 40, 9 to 45, 9 to 50, 9 to55, 9 to 60, 9 to 65, 9 to 70, 9 to 75, 9 to 80, 9 to 85, 9 to 90, 9 to95, 9 to 100, 9 to 110, 9 to 120, 9 to 130, 9 to 140, 9 to 150, 9 to160, 9 to 170, 9 to 180, 9 to 190, 9 to 200, 9 to 210, 9 to 220, 9 to230, 9 to 240, 9 to 250, 9 to 260, 9 to 270, 9 to 280, 9 to 290, 9 to300, 9 to 320, 9 to 340, 9 to 360, 9 to 380, 9 to 400, 9 to 420, 9 to440, 9 to 460, 9 to 480, 9 to 500, 9 to 550, 9 to 600, 9 to 650, 9 to700, 9 to 750, 9 to 800, 9 to 850, 9 to 900, 9 to 1000, 10 to 11, 10 to12, 10 to 13, 10 to 14, 10 to 15, 10 to 16, 10 to 17, 10 to 18, 10 to19, 10 to 20, 10 to 25, 10 to 30, 10 to 35, 10 to 40, 10 to 45, 10 to50, 10 to 55, 10 to 60, 10 to 65, 10 to 70, 10 to 75, 10 to 80, 10 to85, 10 to 90, 10 to 95, 10 to 100, 10 to 110, 10 to 120, 10 to 130, 10to 140, 10 to 150, 10 to 160, 10 to 170, 10 to 180, 10 to 190, 10 to200, 10 to 210, 10 to 220, 10 to 230, 10 to 240, 10 to 250, 10 to 260,10 to 270, 10 to 280, 10 to 290, 10 to 300, 10 to 320, 10 to 340, 10 to360, 10 to 380, 10 to 400, 10 to 420, 10 to 440, 10 to 460, 10 to 480,10 to 500, 10 to 550, 10 to 600, 10 to 650, 10 to 700, 10 to 750, 10 to800, 10 to 850, 10 to 900, 10 to 1000, 20 to 25, 20 to 30, to 35, 20 to40, 20 to 45, 20 to 50, 20 to 55, 20 to 60, 20 to 65, 20 to 70, 20 to75, 20 to 80, 20 to 85, 20 to 90, 20 to 95, 20 to 100, 20 to 110, 20 to120, 20 to 130, 20 to 140, to 150, 20 to 160, 20 to 170, 20 to 180, 20to 190, 20 to 200, 20 to 210, 20 to 220, 20 to 230, 20 to 240, 20 to250, 20 to 260, 20 to 270, 20 to 280, 20 to 290, 20 to 300, 20 to 320,20 to 340, 20 to 360, 20 to 380, 20 to 400, 20 to 420, 20 to 440, 20 to460, 20 to 480, 20 to 500, 20 to 550, 20 to 600, 20 to 650, 20 to 700,20 to 750, 20 to 800, 20 to 850, 20 to 900, 20 to 1000, 30 to 35, 30 to40, 30 to 45, 30 to 50, 30 to 55, 30 to 60, 30 to 65, 30 to 70, 30 to75, 30 to 80, 30 to 85, 30 to 90, 30 to 95, 30 to 100, 30 to 110, 30 to120, 30 to 130, 30 to 140, 30 to 150, 30 to 160, 30 to 170, 30 to 180,30 to 190, 30 to 200, 30 to 210, 30 to 220, 30 to 230, 30 to 240, 30 to250, 30 to 260, 30 to 270, 30 to 280, 30 to 290, 30 to 300, 30 to 320,30 to 340, 30 to 360, 30 to 380, 30 to 400, 30 to 420, 30 to 440, 30 to460, 30 to 480, 30 to 500, 30 to 550, 30 to 600, 30 to 650, 30 to 700,30 to 750, 30 to 800, 30 to 850, 30 to 900, 30 to 1000, 40 to 45, 40 to50, 40 to 55, to 60, 40 to 65, 40 to 70, 40 to 75, 40 to 80, 40 to 85,40 to 90, 40 to 95, 40 to 100, 40 to 110, 40 to 120, 40 to 130, 40 to140, 40 to 150, 40 to 160, 40 to 170, 40 to 180, 40 to 190, 40 to 200,40 to 210, 40 to 220, 40 to 230, 40 to 240, 40 to 250, 40 to 260, 40 to270, 40 to 280, 40 to 290, 40 to 300, 40 to 320, 40 to 340, 40 to 360,40 to 380, 40 to 400, 40 to 420, 40 to 440, 40 to 460, 40 to 480, 40 to500, 40 to 550, 40 to 600, 40 to 650, 40 to 700, 40 to 750, 40 to 800,40 to 850, 40 to 900, 40 to 1000, 50 to 55, 50 to 60, 50 to 65, 50 to70, 50 to 75, 50 to 80, 50 to 85, 50 to 90, 50 to 95, 50 to 100, 50 to110, 50 to 120, 50 to 130, 50 to 140, 50 to 150, 50 to 160, 50 to 170,50 to 180, 50 to 190, 50 to 200, 50 to 210, 50 to 220, 50 to 230, 50 to240, 50 to 250, 50 to 260, 50 to 270, 50 to 280, 50 to 290, 50 to 300,50 to 320, 50 to 340, 50 to 360, 50 to 380, 50 to 400, 50 to 420, 50 to440, 50 to 460, 50 to 480, 50 to 500, 50 to 550, 50 to 600, 50 to 650,50 to 700, 50 to 750, 50 to 800, 50 to 850, 50 to 900, 50 to 1000, 60 to65, 60 to 70, 60 to 75, 60 to 80, 60 to 85, 60 to 90, 60 to 95, 60 to100, 60 to 110, 60 to 120, 60 to 130, 60 to 140, 60 to 150, 60 to 160,60 to 170, 60 to 180, 60 to 190, 60 to 200, 60 to 210, 60 to 220, 60 to230, 60 to 240, 60 to 250, 60 to 260, 60 to 270, 60 to 280, 60 to 290,60 to 300, 60 to 320, 60 to 340, 60 to 360, 60 to 380, 60 to 400, 60 to420, 60 to 440, 60 to 460, 60 to 480, 60 to 500, 60 to 550, 60 to 600,60 to 650, 60 to 700, 60 to 750, 60 to 800, 60 to 850, 60 to 900, 60 to1000, 70 to 75, 70 to 80, 70 to 85, 70 to 90, 70 to 95, 70 to 100, 70 to110, 70 to 120, 70 to 130, 70 to 140, 70 to 150, 70 to 160, 70 to 170,70 to 180, 70 to 190, 70 to 200, 70 to 210, 70 to 220, 70 to 230, 70 to240, 70 to 250, 70 to 260, 70 to 270, 70 to 280, 70 to 290, 70 to 300,70 to 320, 70 to 340, 70 to 360, 70 to 380, 70 to 400, 70 to 420, 70 to440, 70 to 460, 70 to 480, 70 to 500, 70 to 550, 70 to 600, 70 to 650,70 to 700, 70 to 750, 70 to 800, 70 to 850, 70 to 900, 70 to 1000, 80 to85, 80 to 90, 80 to 95, 80 to 100, 80 to 110, 80 to 120, 80 to 130, 80to 140, 80 to 150, 80 to 160, 80 to 170, 80 to 180, 80 to 190, 80 to200, 80 to 210, 80 to 220, 80 to 230, 80 to 240, 80 to 250, 80 to 260,80 to 270, 80 to 280, 80 to 290, 80 to 300, 80 to 320, 80 to 340, 80 to360, 80 to 380, 80 to 400, 80 to 420, 80 to 440, 80 to 460, 80 to 480,80 to 500, 80 to 550, 80 to 600, 80 to 650, 80 to 700, 80 to 750, 80 to800, 80 to 850, 80 to 900, 80 to 1000, 90 to 95, 90 to 100, 90 to 110,90 to 120, 90 to 130, 90 to 140, 90 to 150, 90 to 160, 90 to 170, 90 to180, 90 to 190, 90 to 200, 90 to 210, 90 to 220, 90 to 230, 90 to 240,90 to 250, 90 to 260, 90 to 270, 90 to 280, 90 to 290, 90 to 300, 90 to320, 90 to 340, 90 to 360, 90 to 380, 90 to 400, 90 to 420, 90 to 440,90 to 460, 90 to 480, 90 to 500, 90 to 550, 90 to 600, 90 to 650, 90 to700, 90 to 750, 90 to 800, 90 to 850, 90 to 900, 90 to 1000, 100 to 110,100 to 120, 100 to 130, 100 to 140, 100 to 150, 100 to 160, 100 to 170,100 to 180, 100 to 190, 100 to 200, 100 to 210, 100 to 220, 100 to 230,100 to 240, 100 to 250, 100 to 260, 100 to 270, 100 to 280, 100 to 290,100 to 300, 100 to 320, 100 to 340, 100 to 360, 100 to 380, 100 to 400,100 to 420, 100 to 440, 100 to 460, 100 to 480, 100 to 500, 100 to 550,100 to 600, 100 to 650, 100 to 700, 100 to 750, 100 to 800, 100 to 850,100 to 900, 100 to 1000, 200 to 210, 200 to 220, 200 to 230, 200 to 240,200 to 250, 200 to 260, 200 to 270, 200 to 280, 200 to 290, 200 to 300,200 to 320, 200 to 340, 200 to 360, 200 to 380, 200 to 400, 200 to 420,200 to 440, 200 to 460, 200 to 480, 200 to 500, 200 to 550, 200 to 600,200 to 650, 200 to 700, 200 to 750, 200 to 800, 200 to 850, 200 to 900,200 to 1000, 300 to 320, 300 to 340, 300 to 360, 300 to 380, 300 to 400,300 to 420, 300 to 440, 300 to 460, 300 to 480, 300 to 500, 300 to 550,300 to 600, 300 to 650, 300 to 700, 300 to 750, 300 to 800, 300 to 850,300 to 900, 300 to 1000, 400 to 420, 400 to 440, 400 to 460, 400 to 480,400 to 500, 400 to 550, 400 to 600, 400 to 650, 400 to 700, 400 to 750,400 to 800, 400 to 850, 400 to 900, 400 to 1000, 500 to 550, 500 to 600,500 to 650, 500 to 700, 500 to 750, 500 to 800, 500 to 850, 500 to 900,500 to 1000, 600 to 650, 600 to 700, 600 to 750, 600 to 800, 600 to 850,600 to 900, 600 to 1000, 700 to 750, 700 to 800, 700 to 850, 700 to 900,700 to 1000, 800 to 850, 800 to 900, 800 to 1000, and 900 to 1000chemical derivatizations per μm² on the surface of the hydrogelcapsules, in the interior of the hydrogel capsules, or both, and thehydrogel capsules have pores in a size range of 1 μm to 10 μm, 1 μm to 9μm, 1 μm to 8 μm, 1 μm to 7 μm, 1 μm to 6 μm, 1 μm to 5 μm, 1 μm to 4μm, 1 μm to 3 μm, 1 μm to 2 μm, 1.5 μm to 10 μm, 1.5 μm to 9 μm, 1.5 μmto 8 μm, 1.5 μm to 7 μm, 1.5 μm to 6 μm, 1.5 μm to 5 μm, 1.5 μm to 4 μm,1.5 μm to 3 μm, 1.5 μm to 2 μm, 2 μm to 10 μm, 2 μm to 9 μm, 2 μm to 8μm, 2 μm to 7 μm, 2 μm to 6 μm, 2 μm to 5 μm, 2 μm to 4 μm, 2 μm to 3μm, 2.5 μm to 10 μm, 2.5 μm to 9 μm, 2.5 μm to 8 μm, 2.5 μm to 7 μm, 2.5μm to 6 μm, 2.5 μm to 5 μm, 2.5 μm to 4 μm, 2.5 μm to 3 μm, 3 μm to 10μm, 3 μm to 9 μm, 3 μm to 8 μm, 3 μm to 7 μm, 3 μm to 6 μm, 3 μm to 5μm, 3 μm to 4 μm, 3.5 μm to 10 μm, 3.5 μm to 9 μm, 3.5 μm to 8 μm, 3.5μm to 7 μm, 3.5 μm to 6 μm, 3.5 μm to 5 μm, 3.5 μm to 4 μm, 4 μm to 10μm, 4 μm to 9 μm, 4 μm to 8 μm, 4 μm to 7 μm, 4 μm to 6 μm, 4 μm to 5μm, 4.5 μm to 10 μm, 4.5 μm to 9 μm, 4.5 μm to 8 μm, 4.5 μm to 7 μm, 4.5μm to 6 μm, 4.5 μm to 5 μm, 5 μm to 10 μm, 5 μm to 9 μm, 5 μm to 8 μm, 5μm to 7 μm, 5 μm to 6 μm, 5.5 μm to 10 μm, 5.5 μm to 9 μm, 5.5 μm to 8μm, 5.5 μm to 7 μm, 5.5 μm to 6 μm, 6 μm to 10 μm, 6 μm to 9 μm, 6 μm to8 μm, 6 μm to 7 μm, 6.5 μm to 10 μm, 6.5 μm to 9 μm, 6.5 μm to 8 μm, 6.5μm to 7 μm, 7 μm to 10 μm, 7 μm to 9 μm, 7 μm to 8 μm, 7.5 μm to 10 μm,7.5 μm to 9 μm, 7.5 μm to 8 μm, 8 μm to 10 μm, 8 μm to 9 μm, 8.5 μm to10 μm, 8.5 μm to 9 μm, 9 μm to 10 μm, or 9.5 μm to 10 μm.

In some embodiments, the concentration of surface modifications in therange of 0.1 to 0.2, 0.1 to 0.5, 0.1 to 1, 0.1 to 2, 0.1 to 3, 0.1 to 4,0.1 to 5, 0.1 to 6, 0.1 to 7, 0.1 to 8, 0.1 to 9, 0.1 to 10, 0.1 to 11,0.1 to 12, 0.1 to 13, 0.1 to 14, 0.1 to 15, 0.1 to 16, 0.1 to 17, 0.1 to18, 0.1 to 19, 0.1 to 20, 0.1 to 25, 0.1 to 30, 0.1 to 35, 0.1 to 40,0.1 to 45, 0.1 to 50, 0.1 to 55, 0.1 to 60, 0.1 to 65, 0.1 to 70, 0.1 to75, 0.1 to 80, 0.1 to 85, 0.1 to 90, 0.1 to 95, 0.1 to 100, 0.2 to 0.5,0.0 to 1, 0.2 to 2, 0.2 to 3, 0.2 to 4, 0.2 to 5, 0.2 to 6, 0.2 to 7,0.2 to 8, 0.2 to 9, 0.2 to 10, 0.2 to 11, 0.2 to 12, 0.2 to 13, 0.2 to14, 0.2 to 15, 0.2 to 16, 0.2 to 17, 0.2 to 18, 0.2 to 19, 0.2 to 20,0.2 to 25, 0.2 to 30, 0.2 to 35, 0.2 to 40, 0.2 to 45, 0.2 to 50, 0.2 to55, 0.2 to 60, 0.2 to 65, 0.2 to 70, 0.2 to 75, 0.2 to 80, 0.2 to 85,0.2 to 90, 0.2 to 95, 0.2 to 100, 0.5 to 1, 0.5 to 2, 0.5 to 3, 0.5 to4, 0.5 to 5, 0.5 to 6, 0.5 to 7, 0.5 to 8, 0.5 to 9, 0.5 to 10, 0.5 to11, 0.5 to 12, 0.5 to 13, 0.5 to 14, 0.5 to 15, 0.5 to 16, 0.5 to 17,0.5 to 18, 0.5 to 19, 0.5 to 20, 0.5 to 25, 0.5 to 30, 0.5 to 35, 0.5 to40, 0.5 to 45, 0.5 to 50, 0.5 to 55, 0.5 to 60, 0.5 to 65, 0.5 to 70,0.5 to 75, 0.5 to 80, 0.5 to 85, 0.5 to 90, 0.5 to 95, 0.5 to 100, 1 to2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 1 to11, 1 to 12, 1 to 13, 1 to 14, 1 to 15, 1 to 16, 1 to 17, 1 to 18, 1 to19, 1 to 20, 1 to 25, 1 to 30, 1 to 35, 1 to 40, 1 to 45, 1 to 50, 1 to55, 1 to 60, 1 to 65, 1 to 70, 1 to 75, 1 to 80, 1 to 85, 1 to 90, 1 to95, 1 to 100, 2 to 3, 2 to 4, 2 to 5, 2 to 6, 2 to 7, 2 to 8, 2 to 9, 2to 10, 2 to 11, 2 to 12, 2 to 13, 2 to 14, 2 to 15, 2 to 16, 2 to 17, 2to 18, 2 to 19, 2 to 20, 2 to 25, 2 to 30, 2 to 35, 2 to 40, 2 to 45, 2to 50, 2 to 55, 2 to 60, 2 to 65, 2 to 70, 2 to 75, 2 to 80, 2 to 85, 2to 90, 2 to 95, 2 to 100, 3 to 4, 3 to 5, 3 to 6, 3 to 7, 3 to 8, 3 to9, 3 to 10, 3 to 11, 3 to 12, 3 to 13, 3 to 14, 3 to 15, 3 to 16, 3 to17, 3 to 18, 3 to 19, 3 to 20, 3 to 25, 3 to 30, 3 to 35, 3 to 40, 3 to45, 3 to 50, 3 to 55, 3 to 60, 3 to 65, 3 to 70, 3 to 75, 3 to 80, 3 to85, 3 to 90, 3 to 95, 3 to 100, 4 to 5, 4 to 6, 4 to 7, 4 to 8, 4 to 9,4 to 10, 4 to 11, 4 to 12, 4 to 13, 4 to 14, 4 to 15, 4 to 16, 4 to 17,4 to 18, 4 to 19, 4 to 20, 4 to 25, 4 to 30, 4 to 35, 4 to 40, 4 to 45,4 to 50, 4 to 55, 4 to 60, 4 to 65, 4 to 70, 4 to 75, 4 to 80, 4 to 85,4 to 90, 4 to 95, 4 to 100, 5 to 6, 5 to 7, 5 to 8, 5 to 9, 5 to 10, 5to 11, 5 to 12, 5 to 13, 5 to 14, 5 to 15, 5 to 16, 5 to 17, 5 to 18, 5to 19, 5 to 20, 5 to 25, 5 to 30, 5 to 35, 5 to 40, 5 to 45, 5 to 50, 5to 55, 5 to 60, 5 to 65, 5 to 70, 5 to 75, 5 to 80, 5 to 85, 5 to 90, 5to 95, 5 to 100, 6 to 7, 6 to 8, 6 to 9, 6 to 10, 6 to 11, 6 to 12, 6 to13, 6 to 14, 6 to 15, 6 to 16, 6 to 17, 6 to 18, 6 to 19, 6 to 20, 6 to25, 6 to 30, 6 to 35, 6 to 40, 6 to 45, 6 to 50, 6 to 55, 6 to 60, 6 to65, 6 to 70, 6 to 75, 6 to 80, 6 to 85, 6 to 90, 6 to 95, 6 to 100, 7 to8, 7 to 9, 7 to 10, 7 to 11, 7 to 12, 7 to 13, 7 to 14, 7 to 15, 7 to16, 7 to 17, 7 to 18, 7 to 19, 7 to 20, 7 to 25, 7 to 30, 7 to 35, 7 to40, 7 to 45, 7 to 50, 7 to 55, 7 to 60, 7 to 65, 7 to 70, 7 to 75, 7 to80, 7 to 85, 7 to 90, 7 to 95, 7 to 100, 8 to 9, 8 to 10, 8 to 11, 8 to12, 8 to 13, 8 to 14, 8 to 15, 8 to 16, 8 to 17, 8 to 18, 8 to 19, 8 to20, 8 to 25, 8 to 30, 8 to 35, 8 to 40, 8 to 45, 8 to 50, 8 to 55, 8 to60, 8 to 65, 8 to 70, 8 to 75, 8 to 80, 8 to 85, 8 to 90, 8 to 95, 8 to100, 9 to 10, 9 to 11, 9 to 12, 9 to 13, 9 to 14, 9 to 15, 9 to 16, 9 to17, 9 to 18, 9 to 19, 9 to 20, 9 to 25, 9 to 30, 9 to 35, 9 to 40, 9 to45, 9 to 50, 9 to 55, 9 to 60, 9 to 65, 9 to 70, 9 to 75, 9 to 80, 9 to85, 9 to 90, 9 to 95, 9 to 100, 10 to 11, 10 to 12, 10 to 13, 10 to 14,10 to 15, to 16, 10 to 17, 10 to 18, 10 to 19, 10 to 20, 10 to 25, 10 to30, 10 to 35, 10 to 40, 10 to 45, 10 to 50, 10 to 55, 10 to 60, 10 to65, 10 to 70, 10 to 75, 10 to 80, 10 to 85, 10 to 90, 10 to 95, 10 to100, 20 to 25, 20 to 30, 20 to 35, 20 to 40, 20 to 45, 20 to 50, 20 to55, to 60, 20 to 65, 20 to 70, 20 to 75, 20 to 80, 20 to 85, 20 to 90,20 to 95, 20 to 100, 30 to 35, 30 to 40, 30 to 45, 30 to 50, 30 to 55,30 to 60, 30 to 65, 30 to 70, 30 to 75, 30 to 80, 30 to 85, 30 to 90, 30to 95, 30 to 100, 40 to 45, 40 to 50, 40 to 55, 40 to 60, 40 to 65, to70, 40 to 75, 40 to 80, 40 to 85, 40 to 90, 40 to 95, 40 to 100, 50 to55, 50 to 60, 50 to 65, 50 to 70, 50 to 75, 50 to 80, 50 to 85, 50 to90, 50 to 95, 50 to 100, 60 to 65, 60 to 70, 60 to 75, 60 to 80, 60 to85, 60 to 90, 60 to 95, 60 to 100, 70 to 75, 70 to 80, 70 to 85, 70 to90, 70 to 95, 70 to 100, 80 to 85, 80 to 90, 80 to 95, 80 to 100, 90 to95, 90 to 100 percent, and the capsules or products have pores in a sizerange of 1 μm to 10 μm, 1 μm to 9 μm, 1 μm to 8 μm, 1 μm to 7 μm, 1 μmto 6 μm, 1 μm to 5 μm, 1 μm to 4 μm, 1 μm to 3 μm, 1 μm to 2 μm, 1.5 μmto 10 μm, 1.5 μm to 9 μm, 1.5 μm to 8 μm, 1.5 μm to 7 μm, 1.5 μm to 6μm, 1.5 μm to 5 μm, 1.5 μm to 4 μm, 1.5 μm to 3 μm, 1.5 μm to 2 μm, 2 μmto 10 μm, 2 μm to 9 μm, 2 μm to 8 μm, 2 μm to 7 μm, 2 μm to 6 μm, 2 μmto 5 μm, 2 μm to 4 μm, 2 μm to 3 μm, 2.5 μm to 10 μm, 2.5 μm to 9 μm,2.5 μm to 8 μm, 2.5 μm to 7 μm, 2.5 μm to 6 μm, 2.5 μm to 5 μm, 2.5 μmto 4 μm, 2.5 μm to 3 μm, 3 μm to μm, 3 μm to 9 μm, 3 μm to 8 μm, 3 μm to7 μm, 3 μm to 6 μm, 3 μm to 5 μm, 3 μm to 4 μm, 3.5 μm to 10 μm, 3.5 μmto 9 μm, 3.5 μm to 8 μm, 3.5 μm to 7 μm, 3.5 μm to 6 μm, 3.5 μm to 5 μm,3.5 μm to 4 μm, 4 μm to 10 μm, 4 μm to 9 μm, 4 μm to 8 μm, 4 μm to 7 μm,4 μm to 6 μm, 4 μm to 5 μm, 4.5 μm to 10 μm, 4.5 μm to 9 μm, 4.5 μm to 8μm, 4.5 μm to 7 μm, 4.5 μm to 6 μm, 4.5 μm to 5 μm, 5 μm to 10 μm, 5 μmto 9 μm, 5 μm to 8 μm, 5 μm to 7 μm, 5 μm to 6 μm, 5.5 μm to 10 μm, 5.5μm to 9 μm, 5.5 μm to 8 μm, 5.5 μm to 7 μm, 5.5 μm to 6 μm, 6 μm to 10μm, 6 μm to 9 μm, 6 μm to 8 μm, 6 μm to 7 μm, 6.5 μm to 10 μm, 6.5 μm to9 μm, 6.5 μm to 8 μm, 6.5 μm to 7 μm, 7 μm to μm, 7 μm to 9 μm, 7 μm to8 μm, 7.5 μm to 10 μm, 7.5 μm to 9 μm, 7.5 μm to 8 μm, 8 μm to 10 μm, 8μm to 9 μm, 8.5 μm to 10 μm, 8.5 μm to 9 μm, 9 μm to 10 μm, or 9.5 μm to10 μm.

In some embodiments, the hydrogel capsule is provided as a preparationand at least 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95% or 100% of the hydrogel capsules in the preparation have acombination of pore size and derivatization density or concentration ofsurface modifications described herein.

In some embodiments, the hydrogel capsules are in a size range of 1 mmto 8 mm, 1 mm to 6 mm, 1 mm to 5 mm, 1 mm to 4 mm, 1 mm to 3 mm, 1 mm to2 mm, 1 mm to 1.5 mm, 1.5 mm to 8 mm, 1.5 mm to 6 mm, 1.5 mm to 5 mm,1.5 mm to 4 mm, 1.5 mm to 3 mm, 1.5 mm to 2 mm, 2 mm to 8 mm, 2 mm to 7mm, 2 mm to 6 mm, 2 mm to 5 mm, 2 mm to 4 mm, 2 mm to 3 mm, 2.5 mm to 8mm, 2.5 mm to 7 mm, 2.5 mm to 6 mm, 2.5 mm to 5 mm, 2.5 mm to 4 mm, 2.5mm to 3 mm, 3 mm to 8 mm, 3 mm to 7 mm, 3 mm to 6 mm, 3 mm to 5 mm, 3 mmto 4 mm, 3.5 mm to 8 mm, 3.5 mm to 7 mm, 3.5 mm to 6 mm, 3.5 mm to 5 mm,3.5 mm to 4 mm, 4 mm to 8 mm, 4 mm to 7 mm, 4 mm to 6 mm, 4 mm to 5 mm,4.5 mm to 8 mm, 4.5 mm to 7 mm, 4.5 mm to 6 mm, 4.5 mm to 5 mm, 5 mm to8 mm, 5 mm to 7 mm, 5 mm to 6 mm, 5.5 mm to 8 mm, 5.5 mm to 7 mm, 5.5 mmto 6 mm, 6 mm to 8 mm, 6 mm to 7 mm, 6.5 mm to 8 mm, 6.5 mm to 7 mm, 7mm to 8 mm, or 7.5 mm to 8 mm, have pores in a size range of 0.1 μm to10 μm, 0.1 μm to 9 μm, 0.1 μm to 8 μm, 0.1 μm to 7 μm, 0.1 μm to 6 μm,0.1 μm to 5 μm, 0.1 μm to 4 μm, 0.1 μm to 3 μm, 0.1 μm to 2 μm, 0.15 μmto 10 μm, 0.15 μm to 9 μm, 0.15 μm to 8 μm, 0.15 μm to 7 μm, 0.15 μm to6 μm, 0.15 μm to 5 μm, 0.15 μm to 4 μm, 0.15 μm to 3 μm, 0.15 μm to 2μm, 0.2 μm to 10 μm, 0.2 μm to 9 μm, 0.2 μm to 8 μm, 0.2 μm to 7 μm, 0.2μm to 6 μm, 0.2 μm to 5 μm, 0.2 μm to 4 μm, 0.2 μm to 3 μm, 0.25 μm to10 μm, 0.25 μm to 9 μm, 0.25 μm to 8 μm, 0.25 μm to 7 μm, 0.25 μm to 6μm, 0.25 μm to 5 μm, 0.25 μm to 4 μm, 0.25 μm to 3 μm, 0.3 μm to 10 μm,0.3 μm to 9 μm, 0.3 μm to 8 μm, 0.3 μm to 7 μm, 0.3 μm to 6 μm, 0.3 μmto 5 μm, 0.3 μm to 4 μm, 0.35 μm to 10 μm, 0.35 μm to 9 μm, 0.35 μm to 8μm, 0.35 μm to 7 μm, 0.35 μm to 6 μm, 0.35 μm to 5 μm, 0.35 μm to 4 μm,0.4 μm to 10 μm, 0.4 μm to 9 μm, 0.4 μm to 8 μm, 0.4 μm to 7 μm, 0.4 μmto 6 μm, 0.4 μm to 5 μm, 0.45 μm to 10 μm, 0.45 μm to 9 μm, 0.45 μm to 8μm, 0.45 μm to 7 μm, 0.45 μm to 6 μm, 0.45 μm to 5 μm, 0.5 μm to 10 μm,0.5 μm to 9 μm, 0.5 μm to 8 μm, 0.5 μm to 7 μm, 0.5 μm to 6 μm, 0.55 μmto 10 μm, 0.55 μm to 9 μm, 0.55 μm to 8 μm, 0.55 μm to 7 μm, 0.55 μm to6 μm, 0.6 μm to μm, 0.6 μm to 9 μm, 0.6 μm to 8 μm, 0.6 μm to 7 μm, 0.65μm to 10 μm, 0.65 μm to 9 μm, 0.65 μm to 8 μm, 0.65 μm to 7 μm, 0.7 μmto 10 μm, 0.7 μm to 9 μm, 0.7 μm to 8 μm, 0.75 μm to 10 μm, 0.75 μm to 9μm, 0.75 μm to 8 μm, 0.8 μm to 10 μm, 0.8 μm to 9 μm, 0.85 μm to 10 μm,0.85 μm to 9 μm, 0.9 μm to 10 μm, 0.95 μm to 10 μm, 1 μm to 10 μm, 1 μmto 10 μm, 1 μm to 9 μm, 1 μm to 8 μm, 1 μm to 7 μm, 1 μm to 6 μm, 1 μmto 5 μm, 1 μm to 4 μm, 1 μm to 3 μm, 1 μm to 2 μm, 1.5 μm to 10 μm, 1.5μm to 9 μm, 1.5 μm to 8 μm, 1.5 μm to 7 μm, 1.5 μm to 6 μm, 1.5 μm to 5μm, 1.5 μm to 4 μm, 1.5 μm to 3 μm, 1.5 μm to 2 μm, 2 μm to 10 μm, 2 μmto 9 μm, 2 μm to 8 μm, 2 μm to 7 μm, 2 μm to 6 μm, 2 μm to 5 μm, 2 μm to4 μm, 2 μm to 3 μm, 2.5 μm to 10 μm, 2.5 μm to 9 μm, 2.5 μm to 8 μm, 2.5μm to 7 μm, 2.5 μm to 6 μm, 2.5 μm to 5 μm, 2.5 μm to 4 μm, 2.5 μm to 3μm, 3 μm to 10 μm, 3 μm to 9 μm, 3 μm to 8 μm, 3 μm to 7 μm, 3 μm to 6μm, 3 μm to 5 μm, 3 μm to 4 μm, 3.5 μm to 10 μm, 3.5 μm to 9 μm, 3.5 μmto 8 μm, 3.5 μm to 7 μm, 3.5 μm to 6 μm, 3.5 μm to 5 μm, 3.5 μm to 4 μm,4 μm to 10 μm, 4 μm to 9 μm, 4 μm to 8 μm, 4 μm to 7 μm, 4 μm to 6 μm, 4μm to 5 μm, 4.5 μm to 10 μm, 4.5 μm to 9 μm, 4.5 μm to 8 μm, 4.5 μm to 7μm, 4.5 μm to 6 μm, 4.5 μm to 5 μm, μm to 10 μm, 5 μm to 9 μm, 5 μm to 8μm, 5 μm to 7 μm, 5 μm to 6 μm, 5.5 μm to 10 μm, 5.5 μm to 9 μm, 5.5 μmto 8 μm, 5.5 μm to 7 μm, 5.5 μm to 6 μm, 6 μm to 10 μm, 6 μm to 9 μm, 6μm to 8 μm, 6 μm to 7 μm, 6.5 μm to 10 μm, 6.5 μm to 9 μm, 6.5 μm to 8μm, 6.5 μm to 7 μm, 7 μm to 10 μm, 7 μm to 9 μm, 7 μm to 8 μm, 7.5 μm to10 μm, 7.5 μm to 9 μm, 7.5 μm to 8 μm, 8 μm to 10 μm, 8 μm to 9 μm, 8.5μm to 10 μm, 8.5 μm to 9 μm, 9 μm to 10 μm, or 9.5 μm to 10 μm, and havea density of at least, of less than, or of 0.1, 0.2, 0.5, 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40,45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140,150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280,290, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 550, 600,650, 700, 750, 800, 850, 900, or 1000 chemical modifications per μm² onits surface, interior or both, or have a concentration of surfacemodifications is at least, is less than, or is 0.1, 0.2, 0.3, 0.4, 0.5,0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85,90, 95, or 100 percent.

In some embodiments, the hydrogel capsules are in a size range of 1 mmto 8 mm, 1 mm to 6 mm, 1 mm to 5 mm, 1 mm to 4 mm, 1 mm to 3 mm, 1 mm to2 mm, 1 mm to 1.5 mm, 1.5 mm to 8 mm, 1.5 mm to 6 mm, 1.5 mm to 5 mm,1.5 mm to 4 mm, 1.5 mm to 3 mm, 1.5 mm to 2 mm, 2 mm to 8 mm, 2 mm to 7mm, 2 mm to 6 mm, 2 mm to 5 mm, 2 mm to 4 mm, 2 mm to 3 mm, 2.5 mm to 8mm, 2.5 mm to 7 mm, 2.5 mm to 6 mm, 2.5 mm to 5 mm, 2.5 mm to 4 mm, 2.5mm to 3 mm, 3 mm to 8 mm, 3 mm to 7 mm, 3 mm to 6 mm, 3 mm to 5 mm, 3 mmto 4 mm, 3.5 mm to 8 mm, 3.5 mm to 7 mm, 3.5 mm to 6 mm, 3.5 mm to 5 mm,3.5 mm to 4 mm, 4 mm to 8 mm, 4 mm to 7 mm, 4 mm to 6 mm, 4 mm to 5 mm,4.5 mm to 8 mm, 4.5 mm to 7 mm, 4.5 mm to 6 mm, 4.5 mm to 5 mm, 5 mm to8 mm, 5 mm to 7 mm, 5 mm to 6 mm, 5.5 mm to 8 mm, 5.5 mm to 7 mm, 5.5 mmto 6 mm, 6 mm to 8 mm, 6 mm to 7 mm, 6.5 mm to 8 mm, 6.5 mm to 7 mm, 7mm to 8 mm, or 7.5 mm to 8 mm, have pores in a size range of 1 μm to 10μm, 1 μm to 9 μm, 1 μm to 8 μm, 1 μm to 7 μm, 1 μm to 6 μm, 1 μm to 5μm, 1 μm to 4 μm, 1 μm to 3 μm, 1 μm to 2 μm, 1.5 μm to 10 μm, 1.5 μm to9 μm, 1.5 μm to 8 μm, 1.5 μm to 7 μm, 1.5 μm to 6 μm, 1.5 μm to 5 μm,1.5 μm to 4 μm, 1.5 μm to 3 μm, 1.5 μm to 2 μm, 2 μm to 10 μm, 2 μm to 9μm, 2 μm to 8 μm, 2 μm to 7 μm, 2 μm to 6 μm, 2 μm to μm, 2 μm to 4 μm,2 μm to 3 μm, 2.5 μm to 10 μm, 2.5 μm to 9 μm, 2.5 μm to 8 μm, 2.5 μm to7 μm, 2.5 μm to 6 μm, 2.5 μm to 5 μm, 2.5 μm to 4 μm, 2.5 μm to 3 μm, 3μm to 10 μm, 3 μm to 9 μm, 3 μm to 8 μm, 3 μm to 7 μm, 3 μm to 6 μm, 3μm to 5 μm, 3 μm to 4 μm, 3.5 μm to 10 μm, 3.5 μm to 9 μm, 3.5 μm to 8μm, 3.5 μm to 7 μm, 3.5 μm to 6 μm, 3.5 μm to 5 μm, 3.5 μm to 4 μm, 4 μmto 10 μm, 4 μm to 9 μm, 4 μm to 8 μm, 4 μm to 7 μm, 4 μm to 6 μm, 4 μmto 5 μm, 4.5 μm to 10 μm, 4.5 μm to 9 μm, 4.5 μm to 8 μm, 4.5 μm to 7μm, 4.5 μm to 6 μm, 4.5 μm to 5 μm, 5 μm to 10 μm, 5 μm to 9 μm, 5 μm to8 μm, 5 μm to 7 μm, 5 μm to 6 μm, 5.5 μm to 10 μm, 5.5 μm to 9 μm, 5.5μm to 8 μm, 5.5 μm to 7 μm, 5.5 μm to 6 μm, 6 μm to 10 μm, 6 μm to 9 μm,6 μm to 8 μm, 6 μm to 7 μm, 6.5 μm to 10 μm, 6.5 μm to 9 μm, 6.5 μm to 8μm, 6.5 μm to 7 μm, 7 μm to μm, 7 μm to 9 μm, 7 μm to 8 μm, 7.5 μm to 10μm, 7.5 μm to 9 μm, 7.5 μm to 8 μm, 8 μm to 10 μm, 8 μm to 9 μm, 8.5 μmto 10 μm, 8.5 μm to 9 μm, 9 μm to 10 μm, or 9.5 μm to 10 μm, and have adensity in the range of 0.1 to 0.2, 0.1 to 0.5, 0.1 to 1, 0.1 to 2, 0.1to 3, 0.1 to 4, 0.1 to 5, 0.1 to 6, 0.1 to 7, 0.1 to 8, 0.1 to 9, 0.1 to10, 0.1 to 11, 0.1 to 12, 0.1 to 13, 0.1 to 14, 0.1 to 15, 0.1 to 16,0.1 to 17, 0.1 to 18, 0.1 to 19, 0.1 to 20, 0.1 to 25, 0.1 to 30, 0.1 to35, 0.1 to 40, 0.1 to 45, 0.1 to 50, 0.1 to 55, 0.1 to 60, 0.1 to 65,0.1 to 70, 0.1 to 75, 0.1 to 80, 0.1 to 85, 0.1 to 90, 0.1 to 95, 0.1 to100, 0.1 to 110, 0.1 to 120, 0.1 to 130, 0.1 to 140, 0.1 to 150, 0.1 to160, 0.1 to 170, 0.1 to 180, 0.1 to 190, 0.1 to 200, 0.1 to 210, 0.1 to220, 0.1 to 230, 0.1 to 240, 0.1 to 250, 0.1 to 260, 0.1 to 270, 0.1 to280, 0.1 to 290, 0.1 to 300, 0.1 to 320, 0.1 to 340, 0.1 to 360, 0.1 to380, 0.1 to 400, 0.1 to 420, 0.1 to 440, 0.1 to 460, 0.1 to 480, 0.1 to500, 0.1 to 550, 0.1 to 600, 0.1 to 650, 0.1 to 700, 0.1 to 750, 0.1 to800, 0.1 to 850, 0.1 to 900, 0.1 to 1000, 0.2 to 0.5, 0.0 to 1, 0.2 to2, 0.2 to 3, 0.2 to 4, 0.2 to 5, 0.2 to 6, 0.2 to 7, 0.2 to 8, 0.2 to 9,0.2 to 10, 0.2 to 11, 0.2 to 12, 0.2 to 13, 0.2 to 14, 0.2 to 15, 0.2 to16, 0.2 to 17, 0.2 to 18, 0.2 to 19, 0.2 to 20, 0.2 to 25, 0.2 to 30,0.2 to 35, 0.2 to 40, 0.2 to 45, 0.2 to 50, 0.2 to 55, 0.2 to 60, 0.2 to65, 0.2 to 70, 0.2 to 75, 0.2 to 80, 0.2 to 85, 0.2 to 90, 0.2 to 95,0.2 to 100, 0.2 to 110, 0.2 to 120, 0.2 to 130, 0.2 to 140, 0.2 to 150,0.2 to 160, 0.2 to 170, 0.2 to 180, 0.2 to 190, 0.2 to 200, 0.2 to 210,0.2 to 220, 0.2 to 230, 0.2 to 240, 0.2 to 250, 0.2 to 260, 0.2 to 270,0.2 to 280, 0.2 to 290, 0.2 to 300, 0.2 to 320, 0.2 to 340, 0.2 to 360,0.2 to 380, 0.2 to 400, 0.2 to 420, 0.2 to 440, 0.2 to 460, 0.2 to 480,0.2 to 500, 0.2 to 550, 0.2 to 600, 0.2 to 650, 0.2 to 700, 0.2 to 750,0.2 to 800, 0.2 to 850, 0.2 to 900, 0.2 to 1000, 0.5 to 1, 0.5 to 2, 0.5to 3, 0.5 to 4, 0.5 to 5, 0.5 to 6, 0.5 to 7, 0.5 to 8, 0.5 to 9, 0.5 to10, 0.5 to 11, 0.5 to 12, 0.5 to 13, 0.5 to 14, 0.5 to 15, 0.5 to 16,0.5 to 17, 0.5 to 18, 0.5 to 19, 0.5 to 20, 0.5 to 25, 0.5 to 30, 0.5 to35, 0.5 to 40, 0.5 to 45, 0.5 to 50, 0.5 to 55, 0.5 to 60, 0.5 to 65,0.5 to 70, 0.5 to 75, 0.5 to 80, 0.5 to 85, 0.5 to 90, 0.5 to 95, 0.5 to100, 0.5 to 110, 0.5 to 120, 0.5 to 130, 0.5 to 140, 0.5 to 150, 0.5 to160, 0.5 to 170, 0.5 to 180, 0.5 to 190, 0.5 to 200, 0.5 to 210, 0.5 to220, 0.5 to 230, 0.5 to 240, 0.5 to 250, 0.5 to 260, 0.5 to 270, 0.5 to280, 0.5 to 290, 0.5 to 300, 0.5 to 320, 0.5 to 340, 0.5 to 360, 0.5 to380, 0.5 to 400, 0.5 to 420, 0.5 to 440, 0.5 to 460, 0.5 to 480, 0.5 to500, 0.5 to 550, 0.5 to 600, 0.5 to 650, 0.5 to 700, 0.5 to 750, 0.5 to800, 0.5 to 850, 0.5 to 900, 0.5 to 1000, 1 to 2, 1 to 3, 1 to 4, 1 to5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 1 to 11, 1 to 12, 1 to 13, 1to 14, 1 to 15, 1 to 16, 1 to 17, 1 to 18, 1 to 19, 1 to 20, 1 to 25, 1to 30, 1 to 35, 1 to 40, 1 to 45, 1 to 50, 1 to 55, 1 to 60, 1 to 65, 1to 70, 1 to 75, 1 to 80, 1 to 85, 1 to 90, 1 to 95, 1 to 100, 1 to 110,1 to 120, 1 to 130, 1 to 140, 1 to 150, 1 to 160, 1 to 170, 1 to 180, 1to 190, 1 to 200, 1 to 210, 1 to 220, 1 to 230, 1 to 240, 1 to 250, 1 to260, 1 to 270, 1 to 280, 1 to 290, 1 to 300, 1 to 320, 1 to 340, 1 to360, 1 to 380, 1 to 400, 1 to 420, 1 to 440, 1 to 460, 1 to 480, 1 to500, 1 to 550, 1 to 600, 1 to 650, 1 to 700, 1 to 750, 1 to 800, 1 to850, 1 to 900, 1 to 1000, 2 to 3, 2 to 4, 2 to 5, 2 to 6, 2 to 7, 2 to8, 2 to 9, 2 to 10, 2 to 11, 2 to 12, 2 to 13, 2 to 14, 2 to 15, 2 to16, 2 to 17, 2 to 18, 2 to 19, 2 to 20, 2 to 25, 2 to 30, 2 to 35, 2 to40, 2 to 45, 2 to 50, 2 to 55, 2 to 60, 2 to 65, 2 to 70, 2 to 75, 2 to80, 2 to 85, 2 to 90, 2 to 95, 2 to 100, 2 to 110, 2 to 120, 2 to 130, 2to 140, 2 to 150, 2 to 160, 2 to 170, 2 to 180, 2 to 190, 2 to 200, 2 to210, 2 to 220, 2 to 230, 2 to 240, 2 to 250, 2 to 260, 2 to 270, 2 to280, 2 to 290, 2 to 300, 2 to 320, 2 to 340, 2 to 360, 2 to 380, 2 to400, 2 to 420, 2 to 440, 2 to 460, 2 to 480, 2 to 500, 2 to 550, 2 to600, 2 to 650, 2 to 700, 2 to 750, 2 to 800, 2 to 850, 2 to 900, 2 to1000, 3 to 4, 3 to 5, 3 to 6, 3 to 7, 3 to 8, 3 to 9, 3 to 10, 3 to 11,3 to 12, 3 to 13, 3 to 14, 3 to 15, 3 to 16, 3 to 17, 3 to 18, 3 to 19,3 to 20, 3 to 25, 3 to 30, 3 to 35, 3 to 40, 3 to 45, 3 to 50, 3 to 55,3 to 60, 3 to 65, 3 to 70, 3 to 75, 3 to 80, 3 to 85, 3 to 90, 3 to 95,3 to 100, 3 to 110, 3 to 120, 3 to 130, 3 to 140, 3 to 150, 3 to 160, 3to 170, 3 to 180, 3 to 190, 3 to 200, 3 to 210, 3 to 220, 3 to 230, 3 to240, 3 to 250, 3 to 260, 3 to 270, 3 to 280, 3 to 290, 3 to 300, 3 to320, 3 to 340, 3 to 360, 3 to 380, 3 to 400, 3 to 420, 3 to 440, 3 to460, 3 to 480, 3 to 500, 3 to 550, 3 to 600, 3 to 650, 3 to 700, 3 to750, 3 to 800, 3 to 850, 3 to 900, 3 to 1000, 4 to 5, 4 to 6, 4 to 7, 4to 8, 4 to 9, 4 to 10, 4 to 11, 4 to 12, 4 to 13, 4 to 14, 4 to 15, 4 to16, 4 to 17, 4 to 18, 4 to 19, 4 to 20, 4 to 25, 4 to 30, 4 to 35, 4 to40, 4 to 45, 4 to 50, 4 to 55, 4 to 60, 4 to 65, 4 to 70, 4 to 75, 4 to80, 4 to 85, 4 to 90, 4 to 95, 4 to 100, 4 to 110, 4 to 120, 4 to 130, 4to 140, 4 to 150, 4 to 160, 4 to 170, 4 to 180, 4 to 190, 4 to 200, 4 to210, 4 to 220, 4 to 230, 4 to 240, 4 to 250, 4 to 260, 4 to 270, 4 to280, 4 to 290, 4 to 300, 4 to 320, 4 to 340, 4 to 360, 4 to 380, 4 to400, 4 to 420, 4 to 440, 4 to 460, 4 to 480, 4 to 500, 4 to 550, 4 to600, 4 to 650, 4 to 700, 4 to 750, 4 to 800, 4 to 850, 4 to 900, 4 to1000, 5 to 6, 5 to 7, 5 to 8, 5 to 9, 5 to 10, 5 to 11, 5 to 12, 5 to13, 5 to 14, 5 to 15, 5 to 16, 5 to 17, 5 to 18, 5 to 19, 5 to 20, 5 to25, 5 to 30, 5 to 35, 5 to 40, 5 to 45, 5 to 50, 5 to 55, 5 to 60, 5 to65, 5 to 70, 5 to 75, 5 to 80, 5 to 85, 5 to 90, 5 to 95, 5 to 100, 5 to110, 5 to 120, 5 to 130, 5 to 140, 5 to 150, 5 to 160, 5 to 170, 5 to180, 5 to 190, 5 to 200, 5 to 210, 5 to 220, 5 to 230, 5 to 240, 5 to250, 5 to 260, 5 to 270, 5 to 280, 5 to 290, 5 to 300, 5 to 320, 5 to340, 5 to 360, to 380, 5 to 400, 5 to 420, 5 to 440, 5 to 460, 5 to 480,5 to 500, 5 to 550, 5 to 600, 5 to 650, 5 to 700, 5 to 750, 5 to 800, 5to 850, 5 to 900, 5 to 1000, 6 to 7, 6 to 8, 6 to 9, 6 to 10, 6 to 11, 6to 12, 6 to 13, 6 to 14, 6 to 15, 6 to 16, 6 to 17, 6 to 18, 6 to 19, 6to 20, 6 to 25, 6 to 30, 6 to 35, 6 to 40, 6 to 45, 6 to 50, 6 to 55, 6to 60, 6 to 65, 6 to 70, 6 to 75, 6 to 80, 6 to 85, 6 to 90, 6 to 95, 6to 100, 6 to 110, 6 to 120, 6 to 130, 6 to 140, 6 to 150, 6 to 160, 6 to170, 6 to 180, 6 to 190, 6 to 200, 6 to 210, 6 to 220, 6 to 230, 6 to240, 6 to 250, 6 to 260, 6 to 270, 6 to 280, 6 to 290, 6 to 300, 6 to320, 6 to 340, 6 to 360, 6 to 380, 6 to 400, 6 to 420, 6 to 440, 6 to460, 6 to 480, 6 to 500, 6 to 550, 6 to 600, 6 to 650, 6 to 700, 6 to750, 6 to 800, 6 to 850, 6 to 900, 6 to 1000, 7 to 8, 7 to 9, 7 to 10, 7to 11, 7 to 12, 7 to 13, 7 to 14, 7 to 15, 7 to 16, 7 to 17, 7 to 18, 7to 19, 7 to 20, 7 to 25, 7 to 30, 7 to 35, 7 to 40, 7 to 45, 7 to 50, 7to 55, 7 to 60, 7 to 65, 7 to 70, 7 to 75, 7 to 80, 7 to 85, 7 to 90, 7to 95, 7 to 100, 7 to 110, 7 to 120, 7 to 130, 7 to 140, 7 to 150, 7 to160, 7 to 170, 7 to 180, 7 to 190, 7 to 200, 7 to 210, 7 to 220, 7 to230, 7 to 240, 7 to 250, 7 to 260, 7 to 270, 7 to 280, 7 to 290, 7 to300, 7 to 320, 7 to 340, 7 to 360, 7 to 380, 7 to 400, 7 to 420, 7 to440, 7 to 460, 7 to 480, 7 to 500, 7 to 550, 7 to 600, 7 to 650, 7 to700, 7 to 750, 7 to 800, 7 to 850, 7 to 900, 7 to 1000, 8 to 9, 8 to 10,8 to 11, 8 to 12, 8 to 13, 8 to 14, 8 to 15, 8 to 16, 8 to 17, 8 to 18,8 to 19, 8 to 20, 8 to 25, 8 to 30, 8 to 35, 8 to 40, 8 to 45, 8 to 50,8 to 55, 8 to 60, 8 to 65, 8 to 70, 8 to 75, 8 to 80, 8 to 85, 8 to 90,8 to 95, 8 to 100, 8 to 110, 8 to 120, 8 to 130, 8 to 140, 8 to 150, 8to 160, 8 to 170, 8 to 180, 8 to 190, 8 to 200, 8 to 210, 8 to 220, 8 to230, 8 to 240, 8 to 250, 8 to 260, 8 to 270, 8 to 280, 8 to 290, 8 to300, 8 to 320, 8 to 340, 8 to 360, 8 to 380, 8 to 400, 8 to 420, 8 to440, 8 to 460, 8 to 480, 8 to 500, 8 to 550, 8 to 600, 8 to 650, 8 to700, 8 to 750, 8 to 800, 8 to 850, 8 to 900, 8 to 1000, 9 to 10, 9 to11, 9 to 12, 9 to 13, 9 to 14, 9 to 15, 9 to 16, 9 to 17, 9 to 18, 9 to19, 9 to 20, 9 to 25, 9 to 30, 9 to 35, 9 to 40, 9 to 45, 9 to 50, 9 to55, 9 to 60, 9 to 65, 9 to 70, 9 to 75, 9 to 80, 9 to 85, 9 to 90, 9 to95, 9 to 100, 9 to 110, 9 to 120, 9 to 130, 9 to 140, 9 to 150, 9 to160, 9 to 170, 9 to 180, 9 to 190, 9 to 200, 9 to 210, 9 to 220, 9 to230, 9 to 240, 9 to 250, 9 to 260, 9 to 270, 9 to 280, 9 to 290, 9 to300, 9 to 320, 9 to 340, 9 to 360, 9 to 380, 9 to 400, 9 to 420, 9 to440, 9 to 460, 9 to 480, 9 to 500, 9 to 550, 9 to 600, 9 to 650, 9 to700, 9 to 750, 9 to 800, 9 to 850, 9 to 900, 9 to 1000, 10 to 11, 10 to12, 10 to 13, 10 to 14, 10 to 15, 10 to 16, 10 to 17, 10 to 18, 10 to19, 10 to 20, 10 to 25, 10 to 30, to 35, 10 to 40, 10 to 45, 10 to 50,10 to 55, 10 to 60, 10 to 65, 10 to 70, 10 to 75, 10 to 80, 10 to 85, 10to 90, 10 to 95, 10 to 100, 10 to 110, 10 to 120, 10 to 130, 10 to 140,to 150, 10 to 160, 10 to 170, 10 to 180, 10 to 190, 10 to 200, 10 to210, 10 to 220, 10 to 230, 10 to 240, 10 to 250, 10 to 260, 10 to 270,10 to 280, 10 to 290, 10 to 300, 10 to 320, 10 to 340, 10 to 360, 10 to380, 10 to 400, 10 to 420, 10 to 440, 10 to 460, 10 to 480, 10 to 500,10 to 550, 10 to 600, 10 to 650, 10 to 700, 10 to 750, 10 to 800, 10 to850, 10 to 900, 10 to 1000, 20 to 25, 20 to 30, 20 to 35, 20 to 40, 20to 45, 20 to 50, 20 to 55, 20 to 60, 20 to 65, 20 to 70, 20 to 75, 20 to80, 20 to 85, 20 to 90, 20 to 95, 20 to 100, to 110, 20 to 120, 20 to130, 20 to 140, 20 to 150, 20 to 160, 20 to 170, 20 to 180, 20 to 190,20 to 200, 20 to 210, 20 to 220, 20 to 230, 20 to 240, 20 to 250, 20 to260, 20 to 270, 20 to 280, 20 to 290, 20 to 300, 20 to 320, 20 to 340,20 to 360, 20 to 380, 20 to 400, 20 to 420, 20 to 440, 20 to 460, 20 to480, 20 to 500, 20 to 550, 20 to 600, 20 to 650, 20 to 700, 20 to 750,20 to 800, 20 to 850, 20 to 900, 20 to 1000, 30 to 35, 30 to 40, to 45,30 to 50, 30 to 55, 30 to 60, 30 to 65, 30 to 70, 30 to 75, 30 to 80, 30to 85, 30 to 90, 30 to 95, 30 to 100, 30 to 110, 30 to 120, 30 to 130,30 to 140, 30 to 150, 30 to 160, 30 to 170, 30 to 180, 30 to 190, 30 to200, 30 to 210, 30 to 220, 30 to 230, 30 to 240, 30 to 250, 30 to 260,30 to 270, 30 to 280, 30 to 290, 30 to 300, 30 to 320, 30 to 340, 30 to360, 30 to 380, 30 to 400, 30 to 420, 30 to 440, 30 to 460, 30 to 480,30 to 500, 30 to 550, 30 to 600, 30 to 650, 30 to 700, 30 to 750, 30 to800, 30 to 850, 30 to 900, 30 to 1000, 40 to 45, 40 to 50, 40 to 55, 40to 60, 40 to 65, 40 to 70, 40 to 75, 40 to 80, 40 to 85, 40 to 90, 40 to95, 40 to 100, 40 to 110, 40 to 120, 40 to 130, 40 to 140, 40 to 150, 40to 160, 40 to 170, 40 to 180, 40 to 190, 40 to 200, 40 to 210, 40 to220, 40 to 230, 40 to 240, 40 to 250, 40 to 260, 40 to 270, 40 to 280,40 to 290, 40 to 300, 40 to 320, 40 to 340, 40 to 360, 40 to 380, 40 to400, 40 to 420, 40 to 440, 40 to 460, 40 to 480, 40 to 500, 40 to 550,40 to 600, 40 to 650, 40 to 700, 40 to 750, 40 to 800, 40 to 850, 40 to900, 40 to 1000, 50 to 55, 50 to 60, 50 to 65, 50 to 70, 50 to 75, 50 to80, 50 to 85, 50 to 90, 50 to 95, 50 to 100, 50 to 110, 50 to 120, 50 to130, 50 to 140, 50 to 150, 50 to 160, 50 to 170, 50 to 180, 50 to 190,50 to 200, 50 to 210, 50 to 220, 50 to 230, 50 to 240, 50 to 250, 50 to260, 50 to 270, 50 to 280, 50 to 290, 50 to 300, 50 to 320, 50 to 340,50 to 360, 50 to 380, 50 to 400, 50 to 420, 50 to 440, 50 to 460, 50 to480, 50 to 500, 50 to 550, 50 to 600, 50 to 650, 50 to 700, 50 to 750,50 to 800, 50 to 850, 50 to 900, 50 to 1000, 60 to 65, 60 to 70, 60 to75, 60 to 80, 60 to 85, 60 to 90, 60 to 95, 60 to 100, 60 to 110, 60 to120, 60 to 130, 60 to 140, 60 to 150, 60 to 160, 60 to 170, 60 to 180,60 to 190, 60 to 200, 60 to 210, 60 to 220, 60 to 230, 60 to 240, 60 to250, 60 to 260, 60 to 270, 60 to 280, 60 to 290, 60 to 300, 60 to 320,60 to 340, 60 to 360, 60 to 380, 60 to 400, 60 to 420, 60 to 440, 60 to460, 60 to 480, 60 to 500, 60 to 550, 60 to 600, 60 to 650, 60 to 700,60 to 750, 60 to 800, 60 to 850, 60 to 900, 60 to 1000, 70 to 75, 70 to80, 70 to 85, 70 to 90, 70 to 95, 70 to 100, 70 to 110, 70 to 120, 70 to130, 70 to 140, 70 to 150, 70 to 160, 70 to 170, 70 to 180, 70 to 190,70 to 200, 70 to 210, 70 to 220, 70 to 230, 70 to 240, 70 to 250, 70 to260, 70 to 270, 70 to 280, 70 to 290, 70 to 300, 70 to 320, 70 to 340,70 to 360, 70 to 380, 70 to 400, 70 to 420, 70 to 440, 70 to 460, 70 to480, 70 to 500, 70 to 550, 70 to 600, 70 to 650, 70 to 700, 70 to 750,70 to 800, 70 to 850, 70 to 900, 70 to 1000, 80 to 85, 80 to 90, 80 to95, 80 to 100, 80 to 110, 80 to 120, 80 to 130, 80 to 140, 80 to 150, 80to 160, 80 to 170, 80 to 180, 80 to 190, 80 to 200, 80 to 210, 80 to220, 80 to 230, 80 to 240, 80 to 250, 80 to 260, 80 to 270, 80 to 280,80 to 290, 80 to 300, 80 to 320, 80 to 340, 80 to 360, 80 to 380, 80 to400, 80 to 420, 80 to 440, 80 to 460, 80 to 480, 80 to 500, 80 to 550,80 to 600, 80 to 650, 80 to 700, 80 to 750, 80 to 800, 80 to 850, 80 to900, 80 to 1000, 90 to 95, 90 to 100, 90 to 110, 90 to 120, 90 to 130,90 to 140, 90 to 150, 90 to 160, 90 to 170, 90 to 180, 90 to 190, 90 to200, 90 to 210, 90 to 220, 90 to 230, 90 to 240, 90 to 250, 90 to 260,90 to 270, 90 to 280, 90 to 290, 90 to 300, 90 to 320, 90 to 340, 90 to360, 90 to 380, 90 to 400, 90 to 420, 90 to 440, 90 to 460, 90 to 480,90 to 500, 90 to 550, 90 to 600, 90 to 650, 90 to 700, 90 to 750, 90 to800, 90 to 850, 90 to 900, 90 to 1000, 100 to 110, 100 to 120, 100 to130, 100 to 140, 100 to 150, 100 to 160, 100 to 170, 100 to 180, 100 to190, 100 to 200, 100 to 210, 100 to 220, 100 to 230, 100 to 240, 100 to250, 100 to 260, 100 to 270, 100 to 280, 100 to 290, 100 to 300, 100 to320, 100 to 340, 100 to 360, 100 to 380, 100 to 400, 100 to 420, 100 to440, 100 to 460, 100 to 480, 100 to 500, 100 to 550, 100 to 600, 100 to650, 100 to 700, 100 to 750, 100 to 800, 100 to 850, 100 to 900, 100 to1000, 200 to 210, 200 to 220, 200 to 230, 200 to 240, 200 to 250, 200 to260, 200 to 270, 200 to 280, 200 to 290, 200 to 300, 200 to 320, 200 to340, 200 to 360, 200 to 380, 200 to 400, 200 to 420, 200 to 440, 200 to460, 200 to 480, 200 to 500, 200 to 550, 200 to 600, 200 to 650, 200 to700, 200 to 750, 200 to 800, 200 to 850, 200 to 900, 200 to 1000, 300 to320, 300 to 340, 300 to 360, 300 to 380, 300 to 400, 300 to 420, 300 to440, 300 to 460, 300 to 480, 300 to 500, 300 to 550, 300 to 600, 300 to650, 300 to 700, 300 to 750, 300 to 800, 300 to 850, 300 to 900, 300 to1000, 400 to 420, 400 to 440, 400 to 460, 400 to 480, 400 to 500, 400 to550, 400 to 600, 400 to 650, 400 to 700, 400 to 750, 400 to 800, 400 to850, 400 to 900, 400 to 1000, 500 to 550, 500 to 600, 500 to 650, 500 to700, 500 to 750, 500 to 800, 500 to 850, 500 to 900, 500 to 1000, 600 to650, 600 to 700, 600 to 750, 600 to 800, 600 to 850, 600 to 900, 600 to1000, 700 to 750, 700 to 800, 700 to 850, 700 to 900, 700 to 1000, 800to 850, 800 to 900, 800 to 1000, and 900 to 1000 chemicalderivatizations per μm² on the surface of the hydrogel capsules, in theinterior of the hydrogel capsules, or both.

In some embodiments, the capsules or products are in a size range of 1mm to 8 mm, 1 mm to 6 mm, 1 mm to 5 mm, 1 mm to 4 mm, 1 mm to 3 mm, 1 mmto 2 mm, 1 mm to 1.5 mm, 1.5 mm to 8 mm, 1.5 mm to 6 mm, 1.5 mm to 5 mm,1.5 mm to 4 mm, 1.5 mm to 3 mm, 1.5 mm to 2 mm, 2 mm to 8 mm, 2 mm to 7mm, 2 mm to 6 mm, 2 mm to 5 mm, 2 mm to 4 mm, 2 mm to 3 mm, 2.5 mm to 8mm, 2.5 mm to 7 mm, 2.5 mm to 6 mm, 2.5 mm to 5 mm, 2.5 mm to 4 mm, 2.5mm to 3 mm, 3 mm to 8 mm, 3 mm to 7 mm, 3 mm to 6 mm, 3 mm to 5 mm, 3 mmto 4 mm, 3.5 mm to 8 mm, 3.5 mm to 7 mm, 3.5 mm to 6 mm, 3.5 mm to 5 mm,3.5 mm to 4 mm, 4 mm to 8 mm, 4 mm to 7 mm, 4 mm to 6 mm, 4 mm to 5 mm,4.5 mm to 8 mm, 4.5 mm to 7 mm, 4.5 mm to 6 mm, 4.5 mm to 5 mm, 5 mm to8 mm, 5 mm to 7 mm, 5 mm to 6 mm, 5.5 mm to 8 mm, 5.5 mm to 7 mm, 5.5 mmto 6 mm, 6 mm to 8 mm, 6 mm to 7 mm, 6.5 mm to 8 mm, 6.5 mm to 7 mm, 7mm to 8 mm, or 7.5 mm to 8 mm, have pores in a size range of 1 μm to 10μm, 1 μm to 9 μm, 1 μm to 8 μm, 1 μm to 7 μm, 1 μm to 6 μm, 1 μm to 5μm, 1 μm to 4 μm, 1 μm to 3 μm, 1 μm to 2 μm, 1.5 μm to 10 μm, 1.5 μm to9 μm, 1.5 μm to 8 μm, 1.5 μm to 7 μm, 1.5 μm to 6 μm, 1.5 μm to 5 μm,1.5 μm to 4 μm, 1.5 μm to 3 μm, 1.5 μm to 2 μm, 2 μm to 10 μm, 2 μm to 9μm, 2 μm to 8 μm, 2 μm to 7 μm, 2 μm to 6 μm, 2 μm to μm, 2 μm to 4 μm,2 μm to 3 μm, 2.5 μm to 10 μm, 2.5 μm to 9 μm, 2.5 μm to 8 μm, 2.5 μm to7 μm, 2.5 μm to 6 μm, 2.5 μm to 5 μm, 2.5 μm to 4 μm, 2.5 μm to 3 μm, 3μm to 10 μm, 3 μm to 9 μm, 3 μm to 8 μm, 3 μm to 7 μm, 3 μm to 6 μm, 3μm to 5 μm, 3 μm to 4 μm, 3.5 μm to 10 μm, 3.5 μm to 9 μm, 3.5 μm to 8μm, 3.5 μm to 7 μm, 3.5 μm to 6 μm, 3.5 μm to 5 μm, 3.5 μm to 4 μm, 4 μmto 10 μm, 4 μm to 9 μm, 4 μm to 8 μm, 4 μm to 7 μm, 4 μm to 6 μm, 4 μmto 5 μm, 4.5 μm to 10 μm, 4.5 μm to 9 μm, 4.5 μm to 8 μm, 4.5 μm to 7μm, 4.5 μm to 6 μm, 4.5 μm to 5 μm, 5 μm to 10 μm, 5 μm to 9 μm, 5 μm to8 μm, 5 μm to 7 μm, 5 μm to 6 μm, 5.5 μm to 10 μm, 5.5 μm to 9 μm, 5.5μm to 8 μm, 5.5 μm to 7 μm, 5.5 μm to 6 μm, 6 μm to 10 μm, 6 μm to 9 μm,6 μm to 8 μm, 6 μm to 7 μm, 6.5 μm to 10 μm, 6.5 μm to 9 μm, 6.5 μm to 8μm, 6.5 μm to 7 μm, 7 μm to μm, 7 μm to 9 μm, 7 μm to 8 μm, 7.5 μm to 10μm, 7.5 μm to 9 μm, 7.5 μm to 8 μm, 8 μm to 10 μm, 8 μm to 9 μm, 8.5 μmto 10 μm, 8.5 μm to 9 μm, 9 μm to 10 μm, or 9.5 μm to 10 μm, and have aconcentration of surface modifications in the range of 0.1 to 0.2, 0.1to 0.5, 0.1 to 1, 0.1 to 2, 0.1 to 3, 0.1 to 4, 0.1 to 5, 0.1 to 6, 0.1to 7, 0.1 to 8, 0.1 to 9, 0.1 to 10, 0.1 to 11, 0.1 to 12, 0.1 to 13,0.1 to 14, 0.1 to 15, 0.1 to 16, 0.1 to 17, 0.1 to 18, 0.1 to 19, 0.1 to20, 0.1 to 25, 0.1 to 30, 0.1 to 35, 0.1 to 40, 0.1 to 45, 0.1 to 50,0.1 to 55, 0.1 to 60, 0.1 to 65, 0.1 to 70, 0.1 to 75, 0.1 to 80, 0.1 to85, 0.1 to 90, 0.1 to 95, 0.1 to 100, 0.2 to 0.5, 0.0 to 1, 0.2 to 2,0.2 to 3, 0.2 to 4, 0.2 to 5, 0.2 to 6, 0.2 to 7, 0.2 to 8, 0.2 to 9,0.2 to 10, 0.2 to 11, 0.2 to 12, 0.2 to 13, 0.2 to 14, 0.2 to 15, 0.2 to16, 0.2 to 17, 0.2 to 18, 0.2 to 19, 0.2 to 20, 0.2 to 25, 0.2 to 30,0.2 to 35, 0.2 to 40, 0.2 to 45, 0.2 to 50, 0.2 to 55, 0.2 to 60, 0.2 to65, 0.2 to 70, 0.2 to 75, 0.2 to 80, 0.2 to 85, 0.2 to 90, 0.2 to 95,0.2 to 100, 0.5 to 1, 0.5 to 2, 0.5 to 3, 0.5 to 4, 0.5 to 5, 0.5 to 6,0.5 to 7, 0.5 to 8, 0.5 to 9, 0.5 to 10, 0.5 to 11, 0.5 to 12, 0.5 to13, 0.5 to 14, 0.5 to 15, 0.5 to 16, 0.5 to 17, 0.5 to 18, 0.5 to 19,0.5 to 20, 0.5 to 25, 0.5 to 30, 0.5 to 35, 0.5 to 40, 0.5 to 45, 0.5 to50, 0.5 to 55, 0.5 to 60, 0.5 to 65, 0.5 to 70, 0.5 to 75, 0.5 to 80,0.5 to 85, 0.5 to 90, 0.5 to 95, 0.5 to 100, 1 to 2, 1 to 3, 1 to 4, 1to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 1 to 11, 1 to 12, 1 to13, 1 to 14, 1 to 15, 1 to 16, 1 to 17, 1 to 18, 1 to 19, 1 to 20, 1 to25, 1 to 30, 1 to 35, 1 to 40, 1 to 45, 1 to 50, 1 to 55, 1 to 60, 1 to65, 1 to 70, 1 to 75, 1 to 80, 1 to 85, 1 to 90, 1 to 95, 1 to 100, 2 to3, 2 to 4, 2 to 5, 2 to 6, 2 to 7, 2 to 8, 2 to 9, 2 to 10, 2 to 11, 2to 12, 2 to 13, 2 to 14, 2 to 15, 2 to 16, 2 to 17, 2 to 18, 2 to 19, 2to 20, 2 to 25, 2 to 30, 2 to 35, 2 to 40, 2 to 45, 2 to 50, 2 to 55, 2to 60, 2 to 65, 2 to 70, 2 to 75, 2 to 80, 2 to 85, 2 to 90, 2 to 95, 2to 100, 3 to 4, 3 to 5, 3 to 6, 3 to 7, 3 to 8, 3 to 9, 3 to 10, 3 to11, 3 to 12, 3 to 13, 3 to 14, 3 to 15, 3 to 16, 3 to 17, 3 to 18, 3 to19, 3 to 20, 3 to 25, 3 to 30, 3 to 35, 3 to 40, 3 to 45, 3 to 50, 3 to55, 3 to 60, 3 to 65, 3 to 70, 3 to 75, 3 to 80, 3 to 85, 3 to 90, 3 to95, 3 to 100, 4 to 5, 4 to 6, 4 to 7, 4 to 8, 4 to 9, 4 to 10, 4 to 11,4 to 12, 4 to 13, 4 to 14, 4 to 15, 4 to 16, 4 to 17, 4 to 18, 4 to 19,4 to 20, 4 to 25, 4 to 30, 4 to 35, 4 to 40, 4 to 45, 4 to 50, 4 to 55,4 to 60, 4 to 65, 4 to 70, 4 to 75, 4 to 80, 4 to 85, 4 to 90, 4 to 95,4 to 100, 5 to 6, 5 to 7, 5 to 8, 5 to 9, 5 to 10, 5 to 11, 5 to 12, 5to 13, 5 to 14, 5 to 15, 5 to 16, 5 to 17, 5 to 18, 5 to 19, 5 to 20, 5to 25, 5 to 30, 5 to 35, 5 to 40, 5 to 45, 5 to 50, 5 to 55, 5 to 60, 5to 65, 5 to 70, 5 to 75, 5 to 80, 5 to 85, 5 to 90, 5 to 95, 5 to 100, 6to 7, 6 to 8, 6 to 9, 6 to 10, 6 to 11, 6 to 12, 6 to 13, 6 to 14, 6 to15, 6 to 16, 6 to 17, 6 to 18, 6 to 19, 6 to 20, 6 to 25, 6 to 30, 6 to35, 6 to 40, 6 to 45, 6 to 50, 6 to 55, 6 to 60, 6 to 65, 6 to 70, 6 to75, 6 to 80, 6 to 85, 6 to 90, 6 to 95, 6 to 100, 7 to 8, 7 to 9, 7 to10, 7 to 11, 7 to 12, 7 to 13, 7 to 14, 7 to 15, 7 to 16, 7 to 17, 7 to18, 7 to 19, 7 to 20, 7 to 25, 7 to 30, 7 to 35, 7 to 40, 7 to 45, 7 to50, 7 to 55, 7 to 60, 7 to 65, 7 to 70, 7 to 75, 7 to 80, 7 to 85, 7 to90, 7 to 95, 7 to 100, 8 to 9, 8 to 10, 8 to 11, 8 to 12, 8 to 13, 8 to14, 8 to 15, 8 to 16, 8 to 17, 8 to 18, 8 to 19, 8 to 20, 8 to 25, 8 to30, 8 to 35, 8 to 40, 8 to 45, 8 to 50, 8 to 55, 8 to 60, 8 to 65, 8 to70, 8 to 75, 8 to 80, 8 to 85, 8 to 90, 8 to 95, 8 to 100, 9 to 10, 9 to11, 9 to 12, 9 to 13, 9 to 14, 9 to 15, 9 to 16, 9 to 17, 9 to 18, 9 to19, 9 to 20, 9 to 25, 9 to 30, 9 to 35, 9 to 40, 9 to 45, 9 to 50, 9 to55, 9 to 60, 9 to 65, 9 to 70, 9 to 75, 9 to 80, 9 to 85, 9 to 90, 9 to95, 9 to 100, 10 to 11, 10 to 12, 10 to 13, 10 to 14, 10 to 15, to 16,10 to 17, 10 to 18, 10 to 19, 10 to 20, 10 to 25, 10 to 30, 10 to 35, 10to 40, 10 to 45, 10 to 50, 10 to 55, 10 to 60, 10 to 65, 10 to 70, 10 to75, 10 to 80, 10 to 85, 10 to 90, 10 to 95, 10 to 100, 20 to 25, 20 to30, 20 to 35, 20 to 40, 20 to 45, 20 to 50, 20 to 55, to 60, 20 to 65,20 to 70, 20 to 75, 20 to 80, 20 to 85, 20 to 90, 20 to 95, 20 to 100,30 to 35, 30 to 40, 30 to 45, 30 to 50, 30 to 55, 30 to 60, 30 to 65, 30to 70, 30 to 75, 30 to 80, 30 to 85, 30 to 90, 30 to 95, 30 to 100, 40to 45, 40 to 50, 40 to 55, 40 to 60, 40 to 65, to 70, 40 to 75, 40 to80, 40 to 85, 40 to 90, 40 to 95, 40 to 100, 50 to 55, 50 to 60, 50 to65, 50 to 70, 50 to 75, 50 to 80, 50 to 85, 50 to 90, 50 to 95, 50 to100, 60 to 65, 60 to 70, 60 to 75, 60 to 80, 60 to 85, 60 to 90, 60 to95, 60 to 100, 70 to 75, 70 to 80, 70 to 85, 70 to 90, 70 to 95, 70 to100, 80 to 85, 80 to 90, 80 to 95, 80 to 100, 90 to 95, 90 to 100percent.

In some embodiments, the hydrogel capsule is provided as a preparationand at least 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95% or 100% of the hydrogel capsules in the preparation have acombination of hydrogel capsule size or diameter, pore size, andderivatization density or concentration of surface modificationsdescribed herein.

Because the disclosed modified alginates mediate the reduced fibrosis,capsules made of other materials but coated or encapsulated with themodified alginates is a useful form of capsule for achieving reducedfibrosis. This, the capsules can include capsules and particles made ofa variety of materials that are then coated or encapsulated in alginatethat is or included modified alginate.

The disclosed compositions may be fabricated into artificial organs,such as an artificial pancreas containing encapsulated islet cells. Insome of these embodiments, the cells are encapsulated in a singlehydrogel compartment. In other embodiments, the composition contains aplurality of encapsulated cells dispersed or encapsulated in abiocompatible structure.

C. Therapeutic Agents Included in Hydrogel Capsules

The disclosed hydrogel capsules can include one or more therapeuticagents. Therapeutic agents are any compound, composition, conjugate, orconstruct that can be used to treat a disease, disorder, condition,symptom, etc. Examples of therapeutic agents include cells, tissues,cell products, tissue products, proteins, antibodies, vaccines, vaccinecomponents, antigens, epitopes, drugs, salts, nutrients, buffers, acids,and bases. In some embodiments, the therapeutic agent can be abiological material.

In some embodiments, the hydrogel capsule can include a cell or tissue,e.g., a living cell or tissue, which in some embodiments is encapsulatedin, or coated with, a polymer. In such embodiments, the surface of thepolymer encapsulation or coating is modified with moieties or compoundsdisclosed herein. In some embodiments, the cell can include an exogenousnucleic acid that encodes a therapeutic or diagnostic polypeptide. Insome embodiments the cell or engineered cell is autologous, allogenic,or zenogeneic.

In some embodiments, the cell is a genetically engineered cell thatsecretes a therapeutic agent, such as a protein or hormone for treatinga disease or other condition. In some embodiments, the cell is agenetically engineered cell that secretes a diagnostic agent. In someembodiments, the cell is a stem cell, e.g., an embryonic stem cell,mesenchymal stem cell, hepatic stem cell, or bone marrow stem cell.

1. Biological Materials

Biological material for inclusion in the disclosed hydrogel capsules canbe any biological substance. For example, the biological material can betissue, cells, biological micromolecules, or biological macromolecules.Examples of biological macromolecules include nucleotides, amino acids,cofactors, and hormones. Examples of biological macromolecules includenucleic acids, polypeptides, proteins, and polysaccharides. Examples ofproteins include enzymes, receptors, secretory proteins, structuralproteins, signaling proteins, hormones, and ligands. Any class, type,form, or particular biological material can be used together with anyother classes, types, forms, or particular biological materials.

a. Cells

The cell type chosen for inclusion in the disclosed hydrogel capsulesdepends on the desired therapeutic effect. The cells may be from thepatient (autologous cells), from another donor of the same species(allogeneic cells), or from another species (xenogeneic). Xenogeneiccells are easily accessible, but the potential for rejection and thedanger of possible transmission of viruses to the patient restrictstheir clinical application. Any of these types of cells can be fromnatural sources, stem cells, derived cells, or genetically engineeredcell.

In some embodiments, the cells secrete a therapeutically effectivesubstance, such as a protein or nucleic acid. In some embodiments, thecells produce a metabolic product. In some embodiments, the cellsmetabolize toxic substances. In some embodiments, the cells formstructural tissues, such as skin, bone, cartilage, blood vessels, ormuscle. In some embodiments, the cells are natural, such as islet cellsthat naturally secrete insulin, or hepatocytes that naturally detoxify.In some embodiments, the cells are genetically engineered to express aheterologous protein or nucleic acid and/or overexpress an endogenousprotein or nucleic acid. In some embodiments, the cells are geneticallyengineered to produce a new or different product, which can be anexpression product of the engineered gene(s) or another product, such asa metabolite, produced because of the engineered gene(s).

Types of cells for inclusion in the disclosed hydrogel capsules includecells from natural sources, such as cells from xenotissue, cells from acadaver, and primary cells; stem cells, such as embryonic stem cells,mesenchymal stem cells, and induced pluripotent stem cells; derivedcells, such as cells derived from stem cells, cells from a cell line,reprogrammed cells, reprogrammed stem cells, and cells derived fromreprogrammed stem cells; and genetically engineered cells, such as cellsgenetically engineered to express a protein or nucleic acid, cellsgenetically engineered to produce a metabolic product, and cellsgenetically engineered to metabolize toxic substances.

Types of cells for inclusion in the disclosed hydrogel capsules includeliver cells (e.g., hepatoblasts liver stellate cells, biliary cells, orhepatocytes), insulin producing cells (e.g., pancreatic islet cells,isolated pancreatic beta cells, or insulinoma cells), kidney cells,epidermal cells, epithelial cells, neural cells, including neurons andglial cells (e.g., astrocytes), ganglion cells, retinal epithelialcells, adrenal medulla cells, lung cells, cardiac muscle cells,osteoblast cells, osteoclast cells, bone marrow cells, spleen cells,thymus cells, glandular cells, blood cells (e.g., T cells, B cells,macrophage lineage cells, lymphocytes, or monocytes), endocrinehormone-producing cells (e.g., parathyroid, thyroid, or adrenal cells),cells of intestinal origin and other cells acting primarily tosynthesize and secret or to metabolize materials, endothelial cells(e.g., capillary endothelial cells), fibroblasts (e.g., dermalfibroblasts), myogenic cells, keratinocytes, smooth muscle cells,progenitor cells (e.g., bone marrow progenitor cells, adipose progenitorcells, hepatic precursor cells, endothelia progenitor cells, peripheralblood progenitor cells, or progenitor cells from muscle, skin) marrowstromal cells cell lines (e.g., CHO cells, MDCK cells and PC12 cells).

A preferred cell type is a pancreatic islet cell or otherinsulin-producing cell. Hormone-producing cells can produce one or morehormones, such as insulin, parathyroid hormone, anti-diuretic hormone,oxytocin, growth hormone, prolactin, thyroid stimulating hormone,adrenocorticotropic hormone, follicle-stimulating hormone, lutenizinghormone, thyroxine, calcitonin, aldosterone, cortisol, epinephrine,glucagon, estrogen, progesterone, and testosterone. Geneticallyengineered cells are also suitable for inclusion in the disclosedhydrogel capsules. In some embodiments, the cells are engineered toproduce one or more hormones, such as insulin, parathyroid hormone,anti-diuretic hormone, oxytocin, growth hormone, prolactin, thyroidstimulating hormone, adrenocorticotropic hormone, follicle-stimulatinghormone, lutenizing hormone, thyroxine, calcitonin, aldosterone,cortisol, epinephrine, glucagon, estrogen, progesterone, andtestosterone. In some embodiments, the cells are engineered to secreteblood clotting factors (e.g., for hemophilia treatment) or to secretegrowth hormones. In some embodiments, the cells are contained in naturalor bioengineered tissue. For example, the cells for inclusion in thedisclosed hydrogel capsules are in some embodiments a bioartificialrenal glomerulus. In some embodiments, the cells are suitable fortransplantation into the central nervous system for treatment ofneurodegenerative disease.

Cells can be obtained directly from a donor, from cell culture of cellsfrom a donor, or from established cell culture lines. In the preferredembodiments, cells are obtained directly from a donor, washed andimplanted directly in combination with the polymeric material. The cellsare cultured using techniques known to those skilled in the art oftissue culture.

Cell viability can be assessed using standard techniques, such ashistology and fluorescent microscopy. The function of the implantedcells can be determined using a combination of these techniques andfunctional assays. For example, in the case of hepatocytes, in vivoliver function studies can be performed by placing a cannula into therecipient's common bile duct. Bile can then be collected in increments.Bile pigments can be analyzed by high pressure liquid chromatographylooking for underivatized tetrapyrroles or by thin layer chromatographyafter being converted to azodipyrroles by reaction with diazotizedazodipyrroles ethylanthranilate either with or without treatment withP-glucuronidase. Diconjugated and monoconjugated bilirubin can also bedetermined by thin layer chromatography after alkalinemethanolysis ofconjugated bile pigments. In general, as the number of functioningtransplanted hepatocytes increases, the levels of conjugated bilirubinwill increase. Simple liver function tests can also be done on bloodsamples, such as albumin production. Analogous organ function studiescan be conducted using techniques known to those skilled in the art, asrequired to determine the extent of cell function after implantation.For example, pancreatic islet cells and other insulin-producing cellscan be implanted to achieve glucose regulation by appropriate secretionof insulin. Other endocrine tissues and cells can also be implanted.

The site, or sites, where cells are to be implanted is determined basedon individual need, as is the requisite number of cells. For cellsreplacing or supplementing organ or gland function (for example,hepatocytes or islet cells), the mixture can be injected into themesentery, subcutaneous tissue, retroperitoneum, properitoneal space,and intramuscular space.

The amount and density of cells included in the disclosed hydrogelcapsules will vary depending on the choice of cell and site ofimplantation. In some embodiments, the single cells are present in thehydrogel capsule at a concentration of 0.1×10⁶ to 4×10⁶ cells/ml,preferred 0.5×10⁶ to 2×10⁶ cells/ml. In other embodiments, the cells arepresent as cell aggregates. For example, islet cell aggregates (or wholeislets) preferably contain about 1500-2000 cells for each aggregate of150 μm diameter, which is defined as one islet equivalent (IE).Therefore, in some embodiments, islet cells are present at aconcentration of 100-10000 IE/ml, preferably 200-3,000 IE/ml, morepreferably 500-1500 IE/ml.

i. Islet Cells and Other Insulin-Producing Cells

In preferred embodiments, the disclosed compositions contain islet cellsor other insulin-producing cells. Methods of isolating pancreatic isletcells are known in the art. Field et al., Transplantation 61:1554(1996); Linetsky et al., Diabetes 46:1120 (1997). Fresh pancreatictissue can be divided by mincing, teasing, comminution and/orcollagenase digestion. The islets can then be isolated fromcontaminating cells and materials by washing, filtering, centrifuging orpicking procedures. Methods and apparatus for isolating and purifyingislet cells are described in U.S. Pat. No. 5,447,863 to Langley, U.S.Pat. No. 5,322,790 to Scharp et al., U.S. Pat. No. 5,273,904 to Langley,and U.S. Pat. No. 4,868,121 to Scharp et al. The isolated pancreaticcells may optionally be cultured prior to inclusion in the hydrogelcapsule using any suitable method of culturing islet cells as is knownin the art. See e.g., U.S. Pat. No. 5,821,121 to Brothers. Isolatedcells may be cultured in a medium under conditions that helps toeliminate antigenic components. Insulin-producing cells can also bederived from stem cells and cell lines and can be cells geneticallyengineered to produce insulin.

2. Genetically Engineered Cells

In some embodiments, the disclosed compositions contain cellsgenetically engineered to produce a protein or nucleic acid (e.g., atherapeutic protein or nucleic acid). In these embodiments, the cell canbe, for example, a stem cell (e.g., pluripotent), a progenitor cell(e.g., multipotent or oligopotent), or a terminally differentiated cell(i.e., unipotent). Any of the disclosed cell types can be geneticallyengineered. The cell can be engineered, for example, to contain anucleic acid encoding, for example, a polynucleotide such miRNA or RNAior a polynucleotide encoding a protein. The nucleic acid can be, forexample, integrated into the cells genomic DNA for stable expression orcan be, for example, in an expression vector (e.g., plasmid DNA). Thepolynucleotide or protein can be selected based on the disease to betreated (or effect to be achieved) and the site of transplantation orimplantation. In some embodiments, the polynucleotide or protein isanti-neoplastic. In other embodiments, the polynucleotide or protein isa hormone, growth factor, or enzyme.

Therapeutic agents for secretion by genetically engineered cellsinclude, for example, thyroid stimulating hormone; beneficiallipoproteins such as Apo1; prostacyclin and other vasoactive substances,anti-oxidants and free radical scavengers; soluble cytokine receptors,for example soluble transforming growth factor (TGF) receptor, orcytokine receptor antagonists, for example IL1ra; soluble adhesionmolecules, for example ICAM-1; soluble receptors for viruses, e.g. CD4,CXCR4, CCR5 for HIV; cytokines; elastase inhibitors; bone morphogeneticproteins (BMP) and BMP receptors 1 and 2; endoglin; serotonin receptors;tissue inhibiting metaloproteinases; potassium channels or potassiumchannel modulators; anti-inflammatory factors; angiogenic factorsincluding vascular endothelial growth factor (VEGF), transforming growthfactor (TGF), hepatic growth factor, and hypoxia inducible factor (HIF);polypeptides with neurotrophic and/or anti-angiogenic activity includingciliary neurotrophic factor (CNTF), glial-derived neurotrophic factor(GDNF), nerve growth factor (NGF), brain-derived neurotrophic factor(BDNF), neurotrophin-3, nurturin, fibroblast growth factors (FGFs),endostatin, ATF, fragments of thrombospondin, variants thereof and thelike. More preferred polypeptides are FGFs, such as acidic FGF (aFGF),basic FGF (bFGF), FGF-1 and FGF-2 and endostatin.

In some embodiments, the active agent is a protein or peptide. Examplesof protein active agents include, but are not limited to, cytokines andtheir receptors, as well as chimeric proteins including cytokines ortheir receptors, including, for example tumor necrosis factor alpha andbeta, their receptors and their derivatives; renin; lipoproteins;colchicine; prolactin; corticotrophin; vasopressin; somatostatin;lypressin; pancreozymin; leuprolide; alpha-1-antitrypsin; clottingfactors such as factor VIIIC, factor IX, tissue factor, and vonWillebrands factor; anti-clotting factors such as Protein C; atrialnatriuretic factor; lung surfactant; a plasminogen activator other thana tissue-type plasminogen activator (t-PA), for example a urokinase;bombesin; thrombin; hemopoietic growth factor; enkephalinase; RANTES(regulated on activation normally T-cell expressed and secreted); humanmacrophage inflammatory protein (MIP-1-alpha); a serum albumin such ashuman serum albumin; mullerian-inhibiting substance; relaxin A-chain;relaxin B-chain; prorelaxin; mouse gonadotropin-associated peptide;chorionic gonadotropin; a microbial protein, such as beta-lactamase;DNase; inhibin; activin; receptors for hormones or growth factors;integrin; protein A or D; rheumatoid factors; platelet-derived growthfactor (PDGF); epidermal growth factor (EGF); transforming growth factor(TGF) such as TGF-α and TGF-β, including TGF-β1, TGF-β2, TGF-β3, TGF-β4,or TGF-β5; insulin-like growth factor-I and -II (IGF-I and IGF-II);des(1-3)-IGF-I (brain IGF-I), insulin-like growth factor bindingproteins; CD proteins such as CD-3, CD-4, CD-8, and CD-19;erythropoietin; osteoinductive factors; immunotoxins; an interferon suchas interferon-alpha (e.g., interferon.alpha.2A), -beta, -gamma, -lambdaand consensus interferon; colony stimulating factors (CSFs), e.g.,M-CSF, GM-CSF, and G-CSF; interleukins (ILs), e.g., IL-1 to IL-10;superoxide dismutase; T-cell receptors; surface membrane proteins; decayaccelerating factor; transport proteins; homing receptors; addressins;fertility inhibitors such as the prostaglandins; fertility promoters;regulatory proteins; antibodies (including fragments thereof) andchimeric proteins, such as immunoadhesins; precursors, derivatives,prodrugs and analogues of these compounds, and pharmaceuticallyacceptable salts of these compounds, or their precursors, derivatives,prodrugs and analogues. Suitable proteins or peptides may be native orrecombinant and include, e.g., fusion proteins.

Examples of protein active agents also include CCL1, CCL2 (MCP-1), CCL3(MIP-1α), CCL4 (MIP-1β), CCL5 (RANTES), CCL6, CCL7, CCL8, CCL9 (CCL10),CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20,CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CXCL1 (KC),CXCL2 (SDF1a), CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8 (IL8), CXCL9,CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL17, CX3CL1,XCL1, XCL2, TNFA, TNFB (LTA), TNFC (LTB), TNFSF4, TNFSF5 (CD40LG),TNFSF6, TNFSF7, TNFSF8, TNFSF9, TNFSF10, TNFSF11, TNFSF13B, EDA, IL2,IL15, IL4, IL13, IL7, IL9, IL21, IL3, IL5, IL6, IL11, IL27, IL30, IL31,OSM, LIF, CNTF, CTF1, IL12a, IL12b, IL23, IL27, IL35, IL14, IL16, IL32,IL34, IL10, IL22, IL19, IL20, IL24, IL26, IL29, IFNL1, IFNL2, IFNL3,IL28, IFNA1, IFNA2, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNA10, IFNA13,IFNA14, IFNA16, IFNA17, IFNA21, IFNB1, IFNK, IFNW1, IFNG, ILIA (IL1F1),IL1B (IL1F2), ILIRa (IL1F3), IL1F5 (IL36RN), IL1F6 (IL36A), IL1F7(IL37), IL1F8 (IL36B), IL1F9 (IL36G), IL1F10 (IL38), IL33 (IL1F11), IL18(IL1G), IL17, KITLG, IL25 (IL17E), CSF1 (M-CSF), CSF2 (GM-CSF), CSF3(G-CSF), SPP1, TGFB1, TGFB2, TGFB3, CCL3L1, CCL3L2, CCL3L3, CCL4L1,CCL4L2, IL17B, IL17C, IL17D, IL17F, AIMP1 (SCYE1), MIF, Areg, BC096441,Bmp1, Bmp10, Bmp15, Bmp2, Bmp3, Bmp4, Bmp5, Bmp6, Bmp7, Bmp8a, Bmp8b,Clqtnf4, Ccl21a, Ccl27a, Cd70, Cerl, Cklf, Clcf1, Cmtm2a, Cmtm2b, Cmtm3,Cmtm4, Cmtm5, Cmtm6, Cmtm7, Cmtm8, Crlf1, Ctf2, Ebi3, Edn1, Fam3b, Fas1,Fgf2, Flt31, Gdf10, Gdf11, Gdf15, Gdf2, Gdf3, Gdf5, Gdf6, Gdf7, Gdf9,Gml2597, Gml3271, Gml3275, Gml3276, Gml3280, Gml3283, Gm2564, Gpi1,Grem1, Grem2, Gm, Hmgb1, Ifna11, Ifha12, Ifha9, Ifnab, Ifne, I117a,I123a, I125, I131, Iltifb, Inhba, Lefty 1, Lefty2, Mstn, Nampt, Ndp,Noda1, Pf4, Pglyrp1, Prl7dl, Scg2, Scgb3al, Slurp1, Spp1, Thpo, Tnfsf10,Tnfsf11, Tnfsf12, Tnfsf13, Tnfsf13b, Tnfsf14, Tnfsf15, Tnfsf18, Tnfsf4,Tnfsf8, Tnfsf9, Tslp, Vegfa, Wnt1, Wnt2, Wnt5a, Wnt7a, Xcl1,Epinephrine, Melatonin, Triiodothyronine, Thyroxine, Prostaglandins,Leukotrienes, Prostacyclin, Thromboxane, Islet Amyloid Polypeptide,Müllerian inhibiting factor or hormone, Adiponectin, Corticotropin,Angiotensin, vasopressin, arginine vasopressin, atriopeptin, Brainnatriuretic peptide, Calcitonin, Cholecystokinin, Cortistatin,Enkephalin, Endothelin, Erythropoietin, Follicle-stimulating hormone,Galanin, Gastric inhibitory polypeptide, Gastrin, Ghrelin, Glucagon,Glucagon-like peptide-1, Gonadotropin-releasing hormone, Growthhormone-releasing hormone, Hepcidin, Human chorionic gonadotropin, Humanplacental lactogen, Growth hormone, Inhibin, Insulin, Somatomedin,Leptin, Lipotropin, Luteinizing hormone, Melanocyte stimulating hormone,Motilin, Orexin, Oxytocin, Pancreatic polypeptide, Parathyroid hormone,Pituitary adenylate cyclase-activating peptide, Prolactin, Prolactinreleasing hormone, Relaxin, Renin, Secretin, Somatostatin,Thrombopoietin, Thyrotropin, Thyrotropin-releasing hormone, Vasoactiveintestinal peptide, Androgen, Androgen, acid maltase(alpha-glucosidase), glycogen phosphorylase, glycogen debrancher enzyme,Phosphofructokinase, Phosphoglycerate kinase, Phosphoglycerate mutase,Lactate dehydrogenase, Carnitine palymityl transferase, Carnitine, andMyoadenylate deaminase.

b. Hormones

Hormones to be included in the disclosed hydrogel capsules or, mostpreferably, produced from cells included in the disclosed hydrogelcapsules can be any hormone of interest.

Examples of endocrine hormones include Anti-diuretic Hormone (ADH),which is produced by the posterior pituitary, targets the kidneys, andaffects water balance and blood pressure; Oxytocin, which is produced bythe posterior pituitary, targets the uterus, breasts, and stimulatesuterine contractions and milk secretion; Growth Hormone (GH), which isproduced by the anterior pituitary, targets the body cells, bones,muscles, and affects growth and development; Prolactin, which isproduced by the anterior pituitary, targets the breasts, and maintainsmilk secretions; Growth Hormone-Releasing Hormone (GHRH), which is areleasing hormone of GH and is produced in the arcuate nuclease of thehypothalamus; Thyroid Stimulating Hormone (TSH), which is produced bythe anterior pituitary, targets the thyroid, and regulates thyroidhormones; Thyrotropin-Release Hormone (TRH), which is produced by thehypothalamus and stimulates the release of TSH and prolactin from theanterior pituitary; Adrenocorticotropic Hormone (ACTH), which isproduced by the anterior pituitary, targets the adrenal cortex, andregulates adrenal cortex hormones; Follicle-Stimulating Hormone (FSH),which is produced by the anterior pituitary, targets the ovaries/testes,and stimulates egg and sperm production; Lutenizing Hormone (LH), whichis produced by the anterior pituitary, targets the ovaries/testes, andstimulates ovulation and sex hormone release; LuteinizingHormone-Releasing Hormone (LHRH), also known as Gonadotropin-ReleasingHormone (GnRH), which is synthesized and released from GnRH neuronswithin the hypothalamus and is a trophic peptide hormone responsible forthe release of FSH and LH; Thyroxine, which is produced by the thyroid,targets the body cells, and regulates metabolism; Calcitonin, which isproduced by the thyroid, targets the adrenal cortex, and lowers bloodcalcium; Parathyroid Hormone, which is produced by the parathyroid,targets the bone matrix, and raises blood calcium; Aldosterone, which isproduced by the adrenal cortex, targets the kidney, and regulates waterbalance; Cortisol, which is produced by the adrenal cortex, targets thebody cells, and weakens immune system and stress responses; Epinephrine,which is produced by the adrenal medulla, targets the heart, lungs,liver, and body cells, and affects primary “fight or flight” responses;Glucagon, which is produced by the pancreas, targets the liver body, andraises blood glucose level; Insulin, which is produced by the pancreas,targets body cells, and lowers blood glucose level; Estrogen, which isproduced by the ovaries, targets the reproductive system, and affectspuberty, menstrual, and development of gonads; Progesterone, which isproduced by the ovaries, targets the reproductive system, and affectspuberty, menstrual cycle, and development of gonads; and Testosterone,which is produced by the adrenal gland, testes, targets the reproductivesystem, and affects puberty, development of gonads, and sperm.

In some embodiments, the protein is a growth hormone, such as humangrowth hormone (hGH), recombinant human growth hormone (rhGH), bovinegrowth hormone, methione-human growth hormone, des-phenylalanine humangrowth hormone, and porcine growth hormone; insulin, insulin A-chain,insulin B-chain, and proinsulin; or a growth factor, such as vascularendothelial growth factor (VEGF), nerve growth factor (NGF),platelet-derived growth factor (PDGF), fibroblast growth factor (FGF),epidermal growth factor (EGF), transforming growth factor (TGF), andinsulin-like growth factor-I and -II (IGF-I and IGF-II).

c. Vaccines

The disclosed hydrogel capsules can also be used to provide vaccinecomponents. For example, cells expressing vaccine antigens can beincluded in the hydrogel capsule. A vaccine is a biological preparationthat provides active acquired immunity to a particular disease. Avaccine typically contains the same antigens (or parts of antigents)from a microorganism that causes disease. For example, measles vaccinecontains measles virus. However, the antigens in vaccines are eitherkilled, or weakened to the point that the do not cause disease but theyare strong enough to stimulate the body's immune system so that theimmune system can readily recognize and kill any of microorganisms thatit later encounters (immunity).

An antigen can include any protein or peptide that is foreign to thesubject organism. Preferred antigens can be presented at the surface ofantigen presenting cells (APC) of a subject for surveillance by immuneeffector cells, such as leucocytes expressing the CD4 receptor (CD4 Tcells) and Natural Killer (NK) cells. Typically, the antigen is ofviral, bacterial, protozoan, fungal, or animal origin. In someembodiments the antigen is a cancer antigen. Cancer antigens can beantigens expressed only on tumor cells and/or required for tumor cellsurvival.

Certain antigens are recognized by those skilled in the art asimmuno-stimulatory (i.e., stimulate effective immune recognition) andprovide effective immunity to the organism or molecule from which theyderive. Antigens can be peptides, proteins, polysaccharides,saccharides, lipids, nucleic acids, or combinations thereof. The antigencan be derived from a virus, bacterium, parasite, plant, protozoan,fungus, tissue or transformed cell such as a cancer or leukemic cell andcan be a whole cell or immunogenic component thereof, e.g., cell wallcomponents or molecular components thereof. Suitable antigens are knownin the art and are available from commercial government and scientificsources. The antigens may be purified or partially purified polypeptidesderived from tumors or viral or bacterial sources. The antigens can berecombinant polypeptides produced by expressing DNA encoding thepolypeptide antigen in a heterologous expression system. The antigenscan be DNA encoding all or part of an antigenic protein. Antigens may beprovided as single antigens or may be provided in combination. Antigensmay also be provided as complex mixtures of polypeptides or nucleicacids.

Viral Antigens

A viral antigen can be isolated from any virus including, but notlimited to, a virus from any of the following viral families:Arenavmdae, Arterivirus, Astroviridae, Baculoviridae, Badnavirus,Barnaviridae, Birnaviridae, Bromoviridae, Bunyaviridae, Caliciviridae,CapiUovirus, Carlavirus, Caulimovirus, Circoviridae, Closterovirus,Comoviridae, Coronaviridae (e.g., Coronavirus, such as severe acuterespiratory syndrome (SARS) virus), Corticoviridae, Cystoviridae,Deltavirus, Dianthovirus, Enamovirus, Filoviridae (e.g., Marburg virusand Ebola virus (e.g., Zaire, Reston, Ivory Coast, or Sudan strain)),Fiaviviridae, (e.g., Hepatitis C virus, Dengue virus 1, Dengue virus 2,Dengue virus 3, and Dengue virus 4), Hepadnaviridae, Herpesviridae(e.g., Human herpesvirus 1, 3, 4, 5, and 6, and Cytomegalovirus),Hypoviridae, Iridoviridae, Leviviridae, Lipothrixviridae, Microviridae,Orthomyxoviridae (e.g., Influenzavirus A and B and C), Papovaviridae,Paramyxoviridae (e.g., measles, mumps, and human respiratory syncytialvirus), Parvoviridae, Picornaviridae (e.g, poliovirus, rhinovirus,hepatovirus, and aphthovirus), Poxviridae (e.g., vaccinia and smallpoxvirus), Reoviridae (e.g., rotavirus), Retroviridae (e.g., lentivirus,such as human immunodeficiency virus (HIV) 1 and HIV 2), Rhabdoviridae(for example, rabies virus, measles virus, respiratory syncytial virus,etc.), Togaviridae (for example, rubella virus, dengue virus, etc.), andTotiviridae. Suitable viral antigens also include all or part of Dengueprotein M, Dengue protein E, Dengue D1NS1, Dengue D1NS2, and DengueD1NS3. Viral antigens may be derived from a particular strain such as apapilloma virus, a herpes virus, i.e. herpes simplex 1 and 2; ahepatitis virus, for example, hepatitis A virus (HAV), hepatitis B virus(HBV), hepatitis C virus (HCV), the delta hepatitis D virus (HDV),hepatitis E virus (HEV) and hepatitis G virus (HGV), the tick-borneencephalitis viruses; parainfluenza, varicella-zoster, cytomeglavirus,Epstein-Barr, rotavirus, rhinovirus, adenovirus, coxsackieviruses,equine encephalitis, Japanese encephalitis, yellow fever, Rift Valleyfever, and lymphocytic choriomeningitis.

Bacterial Antigens

Bacterial antigens can originate from any bacteria including, but notlimited to, Actinomyces, Anabaena, Bacillus, Bacteroides, Bellovibrio,Bordetella, Borrelia, Campylobacter, Caulobacter, Chlamydia, Chlorobium,Chromatium, Clostridium, Corynebacterium, Cytophaga, Deinococcus,Escherichia, Francisella, Halobacterium, Heliobacter, Haemophilus,Hemophilus influenza type B (HIB), Hyphomicrobium, Legionella,Leptspirosis, Listeria, Meningococcus A, B and C, Methanobacterium,Micrococcus, Myobacterium, Mycoplasma, Myxococcus, Neisseria,Nitrobacter, Oscillatoria, Prochloron, Proteus, Pseudomonas,Phodospirillum, Rickettsia, Salmonella, Shigella, Spirillum,Spirochaeta, Staphylococcus, Streptococcus, Streptomyces, Sulfolobus,Thermoplasma, Thiobacillus, and Treponema, Vibrio, and Yersinia.

Parasite Antigens

Parasite antigens can be obtained from parasites such as, but notlimited to, an antigen derived from Cryptococcus neoformans, Histoplasmacapsulatum, Candida albicans, Candida tropicalis, Nocardia asteroides,Rickettsia ricketsii, Rickettsia typhi. Mycoplasma pneumoniae,Chlamydial psittaci, Chlamydial trachomatis, Plasmodium falciparum,Trypanosoma brucei, Entamoeba histolytica, Toxoplasma gondii,Trichomonas vaginalis and Schistosoma mansoni. These include Sporozoanantigens, Plasmodian antigens, such as all or part of a Circumsporozoiteprotein, a Sporozoite surface protein, a liver stage antigen, an apicalmembrane associated protein, or a Merozoite surface protein.

Allergens and Environmental Antigens

The antigen can be an allergen or environmental antigen, such as, butnot limited to, an antigen derived from naturally occurring allergenssuch as pollen allergens (tree-, herb, weed-, and grass pollenallergens), insect allergens (inhalant, saliva and venom allergens),animal hair and dandruff allergens, and food allergens. Important pollenallergens from trees, grasses and herbs originate from the taxonomicorders of Fagaies, Oleales, Pinoles and platanaceae including i.a. birch(Betula), alder (Alnus), hazel (Corylus), hornbeam (Carpinus) and olive(Olea), cedar (Cryptomeria and Juniperus), Plane tree (Platanus), theorder of Poales including i.e. grasses of the genera Lolium, Phleum,Poa, Cynodop, Dactylis, Holcus, Phalaris, Secale, and Sorghum, theorders of Asterales and Urticales including i.a. herbs of the generaAmbrosia, Artemisia, and Parietaria. Other allergen antigens that may beused include allergens from house dust mites of the genusDermatophagoides and Euroglyphus, storage mite e.g. Lepidoglyphys,Glycyphagus and Tyrophagus, those from cockroaches, midges and flease.g. Blatella, Periplaneta, Chironomus and Ctenocepphalides, those frommammals such as cat, dog and horse, birds, venom allergens includingsuch originating from stinging or biting insects such as those from thetaxonomic order of Hymenoptera including bees (superfamily Apidae),wasps (superfamily Vespidea), and ants (superfamily Formicoidae). Stillother allergen antigens that may be used include inhalation allergensfrom fungi such as from the genera Alternaria and Cladosporium.

Tumor Antigens

The antigen can be a tumor antigen, including a tumor-associated ortumor-specific antigen, such as, but not limited to, alpha-actinin-4,Bcr-Abl fusion protein, Casp-8, beta-catenin, cdc27, cdk4, cdkn2a,coa-1, dek-can fusion protein, EF2, ETV6-AML1 fusion protein,LDLR-fucosyltransferaseAS fusion protein, HLA-A2, HLA-A11, hsp70-2,KIAAO205, Mart2, Mum-1, 2, and 3, neo-PAP, myosin class I, OS-9,pml-RARa fusion protein, PTPRK, K-ras, N-ras, Triosephosphate isomeras,Bage-1, Gage 3,4,5,6,7, GnTV, Herv-K-mel, Lage-1, Mage-A1,2,3,4,6,10,12,Mage-C2, NA-88, NY-Eso-1/Lage-2, SP17, SSX-2, and TRP2-Int2, MelanA(MART-I), gp100 (Pmel 17), tyrosinase, TRP-1, TRP-2, MAGE-1, MAGE-3,BAGE, GAGE-1, GAGE-2, p15(58), CEA, RAGE, NY-ESO (LAGE), SCP-1,Hom/Mel-40, PRAME, p53, H-Ras, HER-2/neu, BCR-ABL, E2A-PRL, H4-RET,IGH-IGK, MYL-RAR, Epstein Barr virus antigens, EBNA, humanpapillomavirus (HPV) antigens E6 and E7, TSP-180, MAGE-4, MAGE-5,MAGE-6, p185erbB2, p180erbB-3, c-met, nm-23H1, PSA, TAG-72-4, CA 19-9,CA 72-4, CAM 17.1, NuMa, K-ras, b-Catenin, CDK4, Mum-1, p16, TAGE, PSMA,PSCA, CT7, telomerase, 43-9F, 5T4, 791Tgp72, a-fetoprotein, 13HCG,BCA225, BTAA, CA 125, CA 15-3 (CA 27.29YBCAA), CA 195, CA 242, CA-50,CAM43, CD68\KP1, CO-029, FGF-5, G250, Ga733 (EpCAM), HTgp-175, M344,MA-50, MG7-Ag, MOV 18, NB\70K, NY-CO-1, RCAS1, SDCCAG16, TA-90 (Mac-2binding protein\cyclophibn C-associated protein), TAAL6, TAG72, TLP, andTPS.

d. Antibodies

The disclosed hydrogel capsules can also be used to provide antibodies.For example, cells expressing antibodies can be included in the hydrogelcapsule. Antibodies that function by binding directly to one or moreepitopes, other ligands or accessory molecules at the surface ofeukaryote cells, are described. Typically, the antibody or antigenbinding fragment thereof has affinity for a receptor at the surface of aspecific cell type, such as a receptor expressed at the surface ofmacrophage cells.

In some embodiments, the antibody or antigen binding fragment bindsspecifically to an epitope. The epitope can be a linear epitope. Theepitope can be specific to one cell type or can be expressed by multipledifferent cell types. In other embodiments, the antibody or antigenbinding fragment thereof can bind a conformational epitope that includesa 3-D surface feature, shape, or tertiary structure at the surface ofthe target cell.

In some embodiments, the antibody or antigen binding fragment that bindsspecifically to an epitope on the target cell can only bind if theprotein epitope is not bound by a ligand or small molecule.

Various types of antibodies and antibody fragments can be used in thedescribed compositions and methods, including whole immunoglobulin ofany class, fragments thereof, and synthetic proteins containing at leastthe antigen binding variable domain of an antibody. The antibody can bean IgG antibody, such as IgG₁; IgG₂, IgG₃, or IgG₄. An antibody can bein the form of an antigen binding fragment including a Fab fragment,F(ab′)2 fragment, a single chain variable region, and the like.Antibodies can be polyclonal or monoclonal (mAb). Monoclonal antibodiesinclude “chimeric” antibodies in which a portion of the heavy and/orlight chain is identical with or homologous to corresponding sequencesin antibodies derived from a particular species or belonging to aparticular antibody class or subclass, while the remainder of thechain(s) is identical with or homologous to corresponding sequences inantibodies derived from another species or belonging to another antibodyclass or subclass, as well as fragments of such antibodies, so long asthey specifically bind the target antigen and/or exhibit the desiredbiological activity (U.S. Pat. No. 4,816,567; and Morrison, et al.,Proc. Natl. Acad. Sci. USA, 81: 6851-6855 (1984)). The describedantibodies can also be modified by recombinant means, for example bydeletions, additions or substitutions of amino acids, to increaseefficacy of the antibody in mediating the desired function.Substitutions can be conservative substitutions. For example, at leastone amino acid in the constant region of the antibody can be replacedwith a different residue (see, e.g., U.S. Pat. Nos. 5,624,821;6,194,551; WO 9958572; and Angal, et al., Mol. Immunol. 30:105-08(1993)). In some cases changes are made to reduce undesired activities,e.g., complement-dependent cytotoxicity. The antibody can be abi-specific antibody having binding specificities for at least twodifferent antigenic epitopes. In one embodiment, the epitopes are fromthe same antigen. In another embodiment, the epitopes are from twodifferent antigens. Bi-specific antibodies can include bi-specificantibody fragments (see, e.g., Hollinger, et al., Proc. Natl. Acad. Sci.U.S.A., 90:6444-48 (1993); Gruber, et al., J. Immunol., 152:5368(1994)).

Antibodies can be generated by any means known in the art. Exemplarydescriptions means for antibody generation and production includeDelves, Antibody Production: Essential Techniques (Wiley, 1997);Shephard, et al., Monoclonal Antibodies (Oxford University Press, 2000);Goding, Monoclonal Antibodies: Principles And Practice (Academic Press,1993); and Current Protocols In Immunology (John Wiley & Sons, mostrecent edition). Fragments of intact Ig molecules can be generated usingmethods well known in the art, including enzymatic digestion andrecombinant means.

D. Preparation of Modified Alginate Polymers

Modified alginates can be prepared through covalent modification of anyavailable alginate polymer. Covalently modified monomers can beintroduced into alginate polymers using a variety of syntheticprocedures known in the art. In some embodiments, mannuronate andguluronate monomers are covalently modified via esterification and/oramidation of their carboxylic acid moiety. In alternative embodiments,mannuronate and guluronate monomers are covalently modified viaphosphorylation or acetal formation. Stoichiometric variation of thereactants during covalent modification can be used to vary the amount ofcovalently modified monomer incorporated into the modified alginate.

In addition to the reactions discussed below, alternative syntheticmethodologies for the covalent modification of mannuronate andguluronate monomers are known in the art. (see, for example, March,“Advanced Organic Chemistry,” 5^(th) Edition, 2001, Wiley-IntersciencePublication, New York).

I. Modification Via the Carboxylate Moiety of the Mannuronate andGuluronate Monomers

Scheme 1. Representative Reaction Conditions: i. HO—R₁,2-Chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), N-methyl morpholine (NMM);ii. HNR₁R₇, CDMT, NMM.

Mannuronate and guluronate monomers contain a carboxylic acid moietywhich can serve as a point of covalent modification. In preferredembodiments, the carboxylic acid moiety present on one or moremannuronate and/or guluronate residues (1) are reacted as shown inScheme 1.

Mannuronate and guluronate residues (A) can be readily esterified by avariety of methods known in the art, forming covalently modified monomerB. For example, using a Steglich Esterification, mannuronate andguluronate residues (A) can be esterified by reaction with any suitablealcohol (HO—R₁) in the presence of a carbodiimide (for example,N,N′-dicyclohexylcarbodiimide (DCC), N,N′-diisopropylcarbodiimide (DIC),or 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC)) anddimethylaminopyridine (DMAP). In a preferred method, mannuronate andguluronate residues (A) were esterified by reaction with a large molarexcess of an alcohol (HO—R₁) in the presence of2-Chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and N-methyl morpholine(NMM). See, for example, Garrett, C. E. et al. Tetrahedron Lett. 2002;43(23): 4161-4164. Preferred alcohols for use as reagents inesterification include those shown below.

Mannuronate and guluronate residues (A) can also be covalently modifiedvia amidation, forming modified monomer C. For example, mannuronate andguluronate residues (A) can amidated by reaction with any suitable amine(R₁—NH₂) in the presence of a carbodiimide and DMAP. In a preferredmethod, mannuronate and guluronate residues (A) were amidated byreaction with a stoichiometric amount of a suitable amine (R₁—NH₂) inthe presence of CDMT and NMM. Preferred amines for use as reagents inamidation reactions include those shown below.

2. Modification of Mannuronate and Guluronate Monomers Via ClickChemistry

In some embodiments, mannuronate and guluronate monomers are covalentlymodified to introduce a functional group which can be further reactedvia click chemistry.

In preferred embodiments, amidation and/or esterification is used tointroduce a functional group which can further reacted using a1,3-dipolar cycloaddition reaction (i.e. a Huisgen cycloadditionreaction). In a 1,3-dipolar cycloaddition reaction, a first moleculecontaining an azide moiety is reacted with a second molecule containinga terminal or internal alkyne. As shown below, the azide and the alkynegroups undergo an intramolecular 1,3-dipolar cycloaddition reaction,coupling the two molecules together and forming a 1,2,3-triazole ring.

The regiochemistry of 1,3-dipolar cycloadditions reaction can becontrolled by addition of a copper(I) catalyst (formed in situ by thereduction of CuSO₄ with sodium ascorbate) or a ruthenium catalyst (suchas Cp*RuCl(PPh₃)₂, Cp*Ru(COD), or Cp*[RuCl₄]). For example, using acopper catalyst, azides and terminal alkynes can be reacted toexclusively afford the 1,4-regioisomers of 1,2,3-triazoles. Similarly,in the presence of a suitable ruthenium catalyst, azides can be reactedwith internal or terminal alkynes to form exclusively the1,5-regioisomers of 1,2,3-triazoles.

In some embodiments, amidation and/or esterification is used to form acovalently modified monomer containing an alkyne moiety. In theseembodiments, the alkyne moiety present on the covalently modifiedmonomer can be further reacted with a second molecule containing anazide functional group. Upon reaction, the azide and the alkyne groupsundergo an intramolecular 1,3-dipolar cycloaddition reaction forming a1,2,3-triazole ring, coupling the second molecule to the covalentlymodified monomer.

Examples of the alkyne-containing amidation/esterification reactantinclude X_(a)—R_(z)—C≡C—R_(x); wherein X_(a) is —OH or —NH₂; whereinR_(z) is U₁, U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄,U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄,U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃; and whereinR_(x) is hydrogen, U₁, U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃,U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄,U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

In some embodiments,

(1) R_(z) is hydrogen,

(A)

wherein y is an integer from 1 to 11; wherein R^(e) is U_(3j) U₃+Q₁;U₃+Q₂, U₃+Q₃, U₃+Q₄, u₃+Q₂+Q₂, u₃+Q₂+Q₃, U₃+Q₁+Q₄, u₃+Q₂+Q₃, u₃+Q₂+Q₄,u₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃, U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, andU₃+Q₁+Q₂+Q₃+Q₄, preferably U₃+Q₁+Q₃; or together with the carbon atom towhich they are attached, form a 3- to 8-membered unsubstituted orsubstituted carbocyclic or heterocyclic ring; wherein one instance ofR^(e) is or contains X_(a); wherein R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ areindependently C, O, N, or S, wherein the bonds between adjacent R₁₈ toR₂₃ are double or single according to valency, and wherein R₁₈ to R₂₃are bound to none, one, or two hydrogens according to valency; andwherein R₂₄ is independently —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —SO₂—, or NR₄,wherein each R₂₅ is, as valency permits, independently absent, hydrogen,═O, ═S, —OH, —SH, —NR₄, wherein R₄ is 1% U₁+Q₁, U₁+Q2, U₁+Q₃, U₁+Q₄,U₁+Q₁+Q2, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃,U₁+Q₁+Q2+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferablyLJ1+Q1+Qv

(B) —(CH₂)_(s)—R₂₆, wherein s is an integer from 0 to 20; wherein R₂₆ is—X_(a), —O—R₂₇, —S—R₂₇, —(CH₂)_(r)—R₂₇, —CO—R₂₇, or —CHR₂₈R₂₉, wherein ris an integer from 0 to 19; wherein R₂₇ is —X_(a), —(CH₂)_(U)—R₃₀,wherein u is an integer from 0 to 18; wherein R₂₈ is —(CH₂)_(t)—R₃₀, R₂₉is —(CH₂)_(v)—R₃₀, and t and v are integers from 0 to 18, wherein t andv together total 0 to 18; wherein R₃₀ is —X_(a), methyl, —OH, —SH, or—COOH; or

(C)

wherein R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are, independently, hydrogen,U₁, U₁+Q₁, U1+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃; and wherein one instance ofR₃₁, R₃₂, R₃₃, R₃₄, R₃₅, or R₃₆ is or contains X_(a);

wherein R₃₁, R₃₄, R₃₅, and R₃₆ are independently present or absentaccording to valency, and wherein the ring bonds are double or singleaccording to valency;

(2) R_(x) is hydrogen,

(A)

wherein y is an integer from 0-11; wherein R^(e) is independently U_(3j)U₃+Q₁, U₃+Q₂, U₃+Q₃, U₃+Q₄, u₃+Q₂+Q₂, u₃+Q₂+Q₃, U₃+Q₁+Q₄, u₃+Q₂+Q₃,u₃+Q₂+Q₄, U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃, U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄,and U₃+Q₁+Q₂+Q₃+Q₄, preferably U₃+Q₁+Q₃; or together with the carbonatom to which they are attached, form a 3- to 8-membered unsubstitutedor substituted carbocyclic or heterocyclic ring; wherein R₁₈, R₁₉, R₂₀,R₂₁, R₂₂, and R₂₃ are independently C, O, N, or S, wherein the bondsbetween adjacent R₁₈ to R₂₃ are double or single according to valency,and wherein R₁₈ to R₂₃ are bound to none, one, or two hydrogensaccording to valency; and wherein R₂₄ is independently —(CR₂₅R₂₅)_(p)—or —(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q areindependently integers from 0 to 5, wherein X_(b) is absent, —O—, —S—,—SO₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyabsent, hydrogen, ═O, ═S, —OH, —SH, —NR₄, wherein R₄ is U₁, U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃;

(B) —(CH₂)_(s)—R₂₆, wherein s is an integer from 0 to 20; wherein R₂₆ is—O—R₂₇, —S—R₂₇, —(CH₂)_(r)—R₂₇, —CO—R₂₇, or —CHR₂₈R₂₉, wherein r is aninteger from 0 to 19; wherein 5 R₂₇ is —(CH₂)_(U)—R₃₀, wherein u is aninteger from 0 to 18; wherein R₂₈ is —(CH₂)_(t)—R₃₀, R₂₉ is—(CH₂)_(V)—R₃₀, and t and v are integers from 0 to 18, wherein t and vtogether total 0 to 18; wherein R₃₀ is methyl, —OH, —SH, or —COOH; or

(C)

wherein R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are, independently, hydrogen,U₁, U₁+Q₁, U₁+Q2, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃;

wherein R₃₁, R₃₄, R₃₅, and R₃₆ are independently present or absentaccording to valency, and wherein the ring bonds are double or singleaccording to valency; and

(3) wherein R_(z) and R_(x) are not both hydrogen.

Examples of the azide-containing second molecule include R_(w)—N₃,wherein R_(w) is U₁, U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃,U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄,U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

In some embodiments, R_(w) is

(A)

wherein k are independently an integer from 1 to 30; wherein z is aninteger from 0 to 4; wherein X₄ is O or S; wherein R^(a) isindependently U_(3j)U₃+Q₁; U₃+Q₂, U₃+Q₃, U₃+Q₄, u₃+Q₂+Q₂, u₃+Q₂+Q₃,U₃+Q₁+Q₄, u₃+Q₂+Q₃, u₃+Q₂+Q₄, u₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃, U₃+Q₁+Q₂+Q₄,U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄, preferably U₃+Q₁+Q₃; ortogether with the carbon atom to which they are attached, form a 3- to8-membered unsubstituted or substituted carbocyclic, or heterocyclicring; and wherein R₁₀, Rn, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇ areindependently hydrogen, U₁, U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂,U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃,U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferablyU₁+Q₁+Q₂+Q₃; or

(B)

wherein R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are, independently, hydrogen,U₁, U₁+Q₁, U₁+Q2, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃;

wherein R₃₁, R₃₄, R₃₅, and R₃₆ are independently present or absentaccording to valency, and wherein the ring bonds are double or singleaccording to valency.

In alternative embodiments, amidation and/or esterification is used toform a covalently modified monomer containing an azide moiety. In theseembodiments, the azide moiety present on the covalently modified monomercan be further reacted with a second molecule containing a terminal orinternal alkyne. Upon reaction, the azide and the alkyne groups undergoan intramolecular 1,3-dipolar cycloaddition reaction forming a1,2,3-triazole ring, coupling the second molecule to the covalentlymodified monomer.

Examples of the azide-containing amidation/esterification reactantinclude X_(c)—R_(w)—N₃, where X_(c) is —OH or —NH₂ and R_(w) is U₁;U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q2, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

In some embodiments, X_(c) is not —NH₂ and R_(w) is not —CH₂—Ar— or—CH₂—CH₂—(O—CH₂—CH₂)₃.

In some embodiments, R_(w) is

(A)

wherein k are independently an integer from 1 to 30; wherein z is aninteger from 0 to 4; wherein X₄ is O or S; wherein R^(a) isindependently U_(3j) U₃+Q₁, U₃+Q₂, U₃+Q₃, U₃+Q₄, u₃+Q₂+Q₂, u₃+Q₂+Q₃,U₃+Q₁+Q₄, u₃+Q₂+Q₃, u₃+Q₂+Q₄, u₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃, U₃+Q₁+Q₂+Q₄,U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄, preferably U₃+Q₁+Q₃; ortogether with the carbon atom to which they are attached, form a 3- to8-membered unsubstituted or substituted carbocyclic, or heterocyclicring; wherein one instance of R^(a) is or contains X_(c); wherein R₁₀,Rn, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇ are independently U₁; U₁+Q₁, U₁+Q₂,U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃; and wherein one instance of R₁₀,R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, or R₁₇ is or contains X_(c); or

(B)

wherein R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are, independently, hydrogen,U₁, U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃; and wherein one instance ofR₃₁, R₃₂, R₃₃, R₃₄, R₃₅, or R₃₆ is or contains X_(c);

wherein R₃₁, R₃₄, R₃₅, and R₃₆ are independently present or absentaccording to valency, and wherein the ring bonds are double or singleaccording to valency.

Examples of the alkyne-containing second molecule includeR_(z)—C≡C—R_(x), wherein R_(z) and R_(x) are, independently, hydrogen,U₁, U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

In some embodiments, R_(z) and R_(x) are independently hydrogen,

(A)

wherein y is an integer from 0 to 11; wherein R^(e) is independentlyU_(3j) U₃+Q₁, U₃+Q₂, U₃+Q₃, U₃+Q₄, U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄,U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃, U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄,U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄, preferably U₃+Q₁+Q₃; or together withthe carbon atom to which they are attached, form a 3- to 8-memberedunsubstituted or substituted carbocyclic or heterocyclic ring; whereinR₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are independently C, O, N, or S,wherein the bonds between adjacent R₁₈ to R₂₃ are double or singleaccording to valency, and wherein R₁₈ to R₂₃ are bound to none, one, ortwo hydrogens according to valency; and wherein R₂₄ is independently—(CR₂₅R₂₅)_(p)— or —(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and qare independently integers from 0 to 5, wherein X_(b) is absent, —O—,—S—, —SO₂—, or NR₄, wherein each R₂₅ is, as valency permits,independently absent, hydrogen, ═O, ═S, —OH, —SH, —NR₄, wherein R₄ isU₁, U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q_(x)+Q₂+Q₃+Q₄, preferably U₁+Q_(x)+Q₃;

(B) —(CH₂)_(s)—R₂₆, wherein s is an integer from 0 to 20; wherein R₂₆ is—O—R₂₇, —S—R₂₇, —(CH₂)_(r)—R₂₇, —CO—R₂₇, or —CHR₂₈R₂₉, wherein r is aninteger from 0 to 19; wherein R₂₇ is —(CH₂)_(U)—R₃₀, wherein u is aninteger from 0 to 18; wherein R₂₈ is —(CH₂)_(t)—R₃₀, R₂₉ is—(CH₂)_(V)—R₃₀, and t and v are integers from 0 to 18, wherein t and vtogether total 0 to 18; wherein R₃₀ is methyl, —OH, —SH, or —COOH; or

wherein R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are, independently, hydrogen,U₁, U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃;

wherein R₃₁, R₃₄, R₃₅, and R₃₆ are independently present or absentaccording to valency, and wherein the ring bonds are double or singleaccording to valency; and

wherein R_(z) and R_(x) are not both hydrogen.

In some embodiments, the azide moiety can be added to a covalentlymodified monomer containing a leaving group, such as I, Br, OTs, OMs. Insome embodiments, amidation and/or esterification is used to form thecovalently modified monomer containing the leaving group. Examples ofthe leaving group-containing amidation/esterification reactant includeX_(c)—R_(w)-L, where X_(c) is —OH or —NH₂, L is the leaving group, andR_(w) is U₁; U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄,U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄,U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

In some embodiments, X_(c) is not —NH₂ and R_(w) is not —CH₂—Ar— or—CH₂—CH₂—(O—CH₂—CH₂)₃—.

In some embodiments, R_(w) is

(A)

wherein k are independently an integer from 1 to 30; wherein z is aninteger from 0 to 4; wherein X₄ is O or S; wherein R^(a) isindependently U₁; U₁+Q₁; U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃,U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄,U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₃+Q₁+Q₃; ortogether with the carbon atom to which they are attached, form a 3- to8-membered unsubstituted or substituted carbocyclic, or heterocyclicring; wherein one instance of R^(a) is or contains X_(c); wherein R₁₀,Rn, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇ are independently hydrogen, U₁; U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃; and wherein one instance of R₁₀,Rn, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, or R₁₇ is or contains X_(c); or

(B)

wherein R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, and R₃₆ are, independently, hydrogen,U₁, U₁+Q₁, U₁+Q2, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄,and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃; and wherein one instance ofR₃₁, R₃₂, R₃₃, R₃₄, R₃₅, or R₃₆ is or contains X_(c);

wherein R₃₁, R₃₄, R₃₅, and R₃₆ are independently present or absentaccording to valency, and wherein the ring bonds are double or singleaccording to valency.

In some embodiments, X_(c) is not —NH₂ and R_(w) is not —CH₂—Ar— or—CH₂—CH₂—(O—CH₂—CH₂)₃—.

In preferred embodiments, amidation is used to form a covalentlymodified monomer containing an azide moiety. Subsequently, the azidemoiety present on the covalently modified monomer is reacted with asecond molecule containing a terminal or internal alkyne, forming a1,2,3-triazole ring and coupling the second molecule to the covalentlymodified monomer.

As shown in Scheme 2, different strategies can be employed to preparecovalently modified monomers containing an azide moiety.

For example, mannuronate and guluronate residues (A) can amidated byreaction with an amine substituted with an azide moiety (for example,11-Azido-3,6,9-trioxaundecan-1-amine) in the presence of a carbodiimideand DMAP, forming azide-functionalized modified monomer F in a singlesynthetic step. Alternatively, mannuronate and guluronate residues (A)can amidated by reaction with an amine substituted with any moiety whichcan be readily transformed into an azide. For example, mannuronate andguluronate residues can be amidated by reaction with 4-iodobenzylaminein the presence of a carbodiimide and DMAP, forming iodo-functionalizedmonomer D. The iodine moiety can then be readily converted to the azide,for example by treatment with sodium azide.

Subsequently, the azide-functionalized monomers can be reacted with amolecule containing an alkyne functionality. For example,azide-functionalized monomers F and E can be reacted with a moleculecontaining a terminal alkyne functionality in the presence of acopper(I) catalyst (formed in situ by the reduction of CuSO₄ with sodiumascorbate), forming covalently modified monomers G and H.

Alkynes for use as reagents in 1,3-dipolarcycloaddition reactionsinclude alkynes having side groups corresponding to of the moietiesdescribed herein for any of the organic groups, R groups, andsubstituents. For example, the alkynes can have side groupscorresponding to of the moieties described herein for R₈ and R₀.

In some embodiments, alkynes for use as reagents in1,3-dipolarcycloaddition reactions can be

R₆₂—C≡C—R₆₃,   Formula XVII

wherein R₆₂ and R₄₃ are independently hydrogen, or an organic groupingcontaining any number of carbon atoms, 1-30 carbon atoms, 1-20 carbonatoms, or 1-14 carbon atoms, and optionally including one or moreheteroatoms such as oxygen, sulfur, or nitrogen grouping in linear,branched, or cyclic structural formats, representative R₆₂ and R₆₃organic groupings being those present in U₁, U₁+Q₁; U₁+Q₂, U₁+Q₃, U₁+Q₄,U₄+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃,U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferablyU₁+Q₁+Q₃.

In some embodiments, R₆₂ and R₄₃ are independently hydrogen, U₁, U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

In some embodiments, R₆₂ and R₆₃ are independently hydrogen, amino,hydroxyl, thiol, oxo, phosphate, or

In some embodiments, R₆₂ and R₆₃ are independently hydrogen, amino,hydroxyl, thiol, oxo, phosphate, or J₂.

In some embodiments, R₆₂ and R₆₃ are independently,

wherein y is an integer from 0-11; wherein w is an integer from 0-9;wherein k is an integer from 0 to 20;

wherein R^(d) and R^(e) are independently absent, U₃, U₃+Q₁; U₃+Q₂,U₃+Q₃, U₃+Q₄, U₃+Q₂+Q₂, u₃+Q₂+Q₃, U₃+Q₁+Q₄, u₃+Q₂+Q₃, u₃+Q₂+Q₄,u₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃, U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, andU₃+Q₁+Q₂+Q₃+Q₄, preferably U₃+Q₁+Q₃; or together with the carbon atom towhich they are attached, form a 3- to 8-membered unsubstituted orsubstituted carbocyclic or heterocyclic ring;

wherein X_(d) are independently absent, O, or S;

wherein R^(c) is absent, hydrogen, U_(3j) U₃+Q₁; U₃+Q₂, U₃+Q₃, U₃+Q₄,U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃,U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄, preferablyU₃+Q₁+Q₃;

wherein R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are independently C, O, N, S,S(O), or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₃ are doubleor single according to valency, and wherein R₁₈ to R₂₃ are bound tonone, one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—,—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyabsent, hydrogen, ═O, ═S, —OH, —SH, or —NR₄, wherein R₄ is U₁, U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃; and

wherein R₁₀, Rn, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independentlyhydrogen, U₁, U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄,U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄,U₁+Q₂+Q₃+Q₄, and U₁+Q_(x)+Q₂+Q₃+Q₄, preferably U₁+Q_(x)+Q₃.

In some embodiments, Rb₂ and R₄₃ are independently,

wherein y is an integer from 0-11; wherein w is an integer from 0-9;

wherein R^(d) and R^(e) are independently absent, U_(3j) U₃+Q₁; U₃+Q₂,U₃+Q₃, U₃+Q₄, u₃+Q₂+Q₂, u₃+Q₂+Q₃, U₃+Q₁+Q₄, u₃+Q₂+Q₃, u₃+Q₂+Q₄,u₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃, U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, andU₃+Q₁+Q₂+Q₃+Q₄, preferably U₃+Q₁+Q₃; or together with the carbon atom towhich they are attached, form a 3- to 8-membered unsubstituted orsubstituted carbocyclic or heterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are independently C, O, N, S,S(O), or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₃ are doubleor single according to valency, and wherein R₁₈ to R₂₃ are bound tonone, one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—,—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyabsent, hydrogen, ═O, ═S, —OH, —SH, or —NR₄, wherein R₄ is U₁, U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

In some embodiments. R₆₇ and R₆₃ are independentlv.

wherein w is an integer from 0-9;

wherein R^(d) and R^(e) are independently absent, U_(3j) U₃+Q₁; U₃+Q₂,U₃+Q₃, U₃+Q₄, U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄,U₃+Q₃+Q₄, U₃+Q₁+Q₂+Q₃, U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, andU₃+Q₁+Q₂+Q₃+Q₄, preferably U₃+Q₁+Q₃; or together with the carbon atom towhich they are attached, form a 3- to 8-membered unsubstituted orsubstituted carbocyclic or heterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are independently C, O, N, S, S(O),or S(O)₂, wherein the bonds between adjacent R₁₈ to R₂₂ are double orsingle according to valency, and wherein R₁₈ to R₂₂ are bound to none,one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—,—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyabsent, hydrogen, ═O, ═S, —OH, —SH, or —NR₄, wherein R₄ is U₁, U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q2+Q₄,U₄+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q_(x)+Q₂+Q₃+Q₄, preferably U₁+Q_(x)+Q₃.

In some embodiments, R₆₂ and R₆₃ are independently,

wherein w is an integer from 0-9;

wherein R^(d) and R^(e) are independently U_(3j) U₃+Q₁, U₃+Q₂, U₃+Q₃,U₃+Q₄, U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄,U₃+Q₁+Q₂+Q₃, U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄,preferably U₃+Q₁+Q₃; or together with the carbon atom to which they areattached, form a 3- to 8-membered unsubstituted or substitutedcarbocyclic or heterocyclic ring;

wherein R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are independently C or N, whereinthe bonds between adjacent R₁₈ to R₂₂ are double or single according tovalency, wherein one, two, three, or four of R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂are N and the others are C, and wherein R₁₈ to R₂₂ are bound to none,one, or two hydrogens according to valency; and

wherein R₂₄ are independently absent, —(CR₂₅R₂₅)_(p)— or—(CR₂₅R₂₅)_(p)—X_(b)—(CR₂₅R₂₅)_(q)—, wherein p and q are independentlyintegers from 0 to 5, wherein X_(b) is absent, —O—, —S—, —S(O)—,—S(O)₂—, or NR₄, wherein each R₂₅ is, as valency permits, independentlyabsent, hydrogen, ═O, ═S, —OH, —SH, or —NR₄, wherein R₄ is U₁, U₁+Q₁,U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄,U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄, U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, andU₁+Q_(x)+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₃.

In some embodiments, R₆₂ and R₆₃ are independently,

wherein k is an integer from 0 to 20;

wherein X₄ are independently absent, O, or S;

wherein R^(c) is R^(b), absent, hydrogen, U_(3j) U₃+Q₁; U₃+Q₂, U₃+Q₃,U₃+Q₄, U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄,U₃+Q₁+Q2+Q₃, U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₄+Q₂+Q₃+Q₄,preferably U₃+Q₁+Q₃; and

wherein R₁₀, Rn, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independentlyR^(b), hydrogen, U₁, U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃,U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄,U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

In some embodiments, R₆₂ and R₆₃ are independently,

wherein k is an integer from 1 to 20;

wherein X₄ are independently O or S;

wherein R^(c) is R^(b), absent, hydrogen, U_(3j) U₃+Q₁, U₃+Q₂, U₃+Q₃,U₃+Q₄, U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄,U₃+Q₁+Q2+Q₃, U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄,preferably U₃+Q₁+Q₃; and

wherein R₁₀, Rn, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independentlyR^(b), hydrogen, U₁, U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃,U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₄+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄,U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

In some embodiments, R₆₂ and R₆₃ are independently,

wherein k is an integer from 1 to 20;

wherein X₄ are O;

wherein R^(c) is R^(b), absent, hydrogen, U_(3j) U₃+Q₁, U₃+Q₂, U₃+Q₃,U₃+Q₄, U₃+Q₂+Q₂, U₃+Q₂+Q₃, U₃+Q₁+Q₄, U₃+Q₂+Q₃, U₃+Q₂+Q₄, U₃+Q₃+Q₄,U₃+Q₁+Q2+Q₃, U₃+Q₁+Q₂+Q₄, U₃+Q₁+Q₃+Q₄, U₃+Q₂+Q₃+Q₄, and U₃+Q₁+Q₂+Q₃+Q₄,preferably U₃+Q₁+Q₃; and

wherein R₁₀, Rn, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independentlyR^(b), hydrogen, U₁, U₁+Q₁, U₁+Q₂, U₁+Q₃, U₁+Q₄, U₁+Q₁+Q₂, U₁+Q₁+Q₃,U₁+Q₁+Q₄, U₁+Q₂+Q₃, U₁+Q₂+Q₄, U₁+Q₃+Q₄, U₁+Q₁+Q₂+Q₃, U₁+Q₁+Q₂+Q₄,U₁+Q₁+Q₃+Q₄, U₁+Q₂+Q₃+Q₄, and U₁+Q₁+Q₂+Q₃+Q₄, preferably U₁+Q₁+Q₂+Q₃.

In some embodiments of R₁₀, R_(n), R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₃₁,R₃₂, R₃₃, R₃₄, R₃₅, R₃₆, R₃₈, R₃₉, R₄₀, X_(g), and independently incombination with any embodiments of any other relevant substituentclasses, R₁₀, Rn, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅,R₃₆, R₃₈, R₃₉, R₄₀, X_(g) can be, independently, absent, hydrogen, or anorganic grouping containing any number of carbon atoms, 1-30 carbonatoms, 1-20 carbon atoms, or 1-14 carbon atoms, and optionally includingone or more heteroatoms such as oxygen, sulfur, or nitrogen grouping inlinear, branched, or cyclic structural formats, representative R₁₀, Rn,R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, R₃₆, R₃₈, R₃₉,R₄₀, X_(g) organic groupings being those present in U₁+Q₁, U₁+Q₂, U₁+Q3,U₁+Q₄, U₁+Q₅, U₁+Q₁+Q₂, U₁+Q₁+Q₃, U₁+Q₁+Q₄, U₁+Q₁+Q₅, U₁+Q₂+Q₃,U₁+Q₂+Q₄, U₁+Q₂+Q₅, U₁+Q₃+Q₄, U₁+Q₃+Q₅, U₁+Q₄+Q₅, U₁+Q₁+Q₂+Q₃,U₁+Q₁+Q2+Q₄, U₁+Q₁+Q₂+Q₅, U₁+Q₁+Q₃+Q₄, U₁+Q₁+Q₃+Q₅, U₁+Q₁+Q₄+Q₅,U₁+Q₂+Q₃+Q₄, U₁+Q₂+Q₃+Q₅, U₁+Q₂+Q₄+Q₅, U₁+Q₃+Q₄+Q₅, U₁+Q₁+Q₂+Q₃+Q₄,U₁+Q₁+Q₂+Q₃+Q₅, U₁+Q₁+Q₂+Q₄+Q₅, U₁+Q₁+Q₃+Q₄+Q₅, U₁+Q₂+Q₃+Q₄+Q5, orU₁+Q₁+Q₂+Q₃+Q₄, +Q₅.

In some embodiments of R₁₀, Rn, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₃₁, R₃₂,R₃₃, R₃₄, R₃₅, R₃₆, R₃₈, R₃₉, R₄₀, X_(g), and independently incombination with any embodiments of any other relevant substituentclasses, R₁₀, Rn, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅,R₃₆, R₃₈, R₃₉, R₄₀, X_(g) can be, independently, absent, hydrogen, or anorganic grouping containing any number of carbon atoms, 1-30 carbonatoms, 1-20 carbon atoms, or 1-14 carbon atoms, and optionally includingone or more heteroatoms such as oxygen, sulfur, or nitrogen grouping inlinear, branched, or cyclic structural formats, representative R₁₀, Rn,R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, R₃₆, R₃₈, R₃₉,R₄₀, X_(g) organic groupings being those present in U4+Q₁, U4+Q₂, U4+Q₃,U4+Q₄, U4+Q₅, U4+Q₆, U4+Q₇, U4+Q₈, U4+Q₉, U4+Q₁+Q₂, U4+Q₁+Q₃, U4+Q₁+Q₄,U4+Q₁+Q₅, U4+Q₁+Q₆, U4+Q₁+Q₇, U4+Q₁+Q₈, U4+Q₁+Q₉, U4+Q₂+Q₃, U4+Q₂+Q₄,U4+Q₂+Q₅, U4+Q₂+Q₆, U4+Q₂+Q₇, U4+Q₂+Q₈, U4+Q₂+Q9, U4+Q₃+Q₄, U4+Q₃+Q₅,U4+Q₃+Q₆, U4+Q₃+Q₇, U4+Q₃+Q₈, U4+Q₃+Q9, U4+Q₄+Q₅, U4+Q₄+Q₆, U4+Q₄+Q₇,U4+Q₄+Q₈, U4+Q₄+Q₉, U4+Q₅+Q₆, U4+Q₅+Q₇, U4+Q₅+Q₈, U4+Q₅+Q₉, U4+Q₆+Q₇,U4+Q₆+Q₈, U4+Q₅+Q9, U4+Q₇+Q₈, U4+Q₇+Q₉, U4+Q₈+Q9, U4+Q₁+Q₂+Q₃,U4+Q₁+Q₂+Q₄, U4+Q₁+Q₂+Q₅, U4+Q₁+Q₂+Q₆, U4+Q₁+Q₂+Q₇, U4+Q₁+Q₂+Q₈,U4+Q₁+Q₂+Q9, U4+Q₁+Q₃+Q₄, U4+Q₁+Q₃+Q₅, U4+Q₁+Q₃+Q₆, U4+Q₁+Q₃+Q₇,U4+Q₁+Q₃+Q₈, U4+Q₁+Q₃+Q₉, U4+Q₁+Q₄+Q₅, U4+Q₁+Q₄+Q₆, U4+Q₁+Q₄+Q₇,U4+Q₁+Q₄+Q₅, U4+Q₁+Q₄+Q9, U4+Q₁+Q₅+Q₆, U4+Q₁+Q₅+Q₇, U4+Q₁+Q₅+Q₈,U4+Q₁+Q₅+Q₉, U4+Q₁+Q₆+Q₇, U4+Q₁+Q₆+Q₈, U4+Q₁+Q₆+Q9, U4+Q₁+Q₇+Q₈,U4+Q₁+Q₇+Q9, U4+Q₁+Q₅+Q9, U4+Q₂+Q₃+Q₄, U4+Q₂+Q₃+Q₅, U4+Q₂+Q₃+Q₆,U4+Q₂+Q₃+Q₇, U4+Q₂+Q₃+Q₈, U4+Q₂+Q₃+Q₉, U4+Q₂+Q₄+Q₅, U4+Q₂+Q₄+Q₆,U4+Q₂+Q₄+Q₇, U4+Q₂+Q₄+Q₅, U4+Q₂+Q₄+Q₉, U4+Q₂+Q₅+Q₆, U4+Q₂+Q₅+Q₇,U4+Q₂+Q₅+Q₈, U4+Q₂+Q₅+Q₉, U4+Q₂+Q₆+Q₇, U4+Q₂+Q₆+Q₈, U4+Q₂+Q₆+Q₉,U4+Q₂+Q₇+Q₈, U4+Q₂+Q₇+Q9, U4+Q₂+Q₈+Q9, U4+Q₃+Q₄+Q₅, U4+Q₃+Q₄+Q₆,U4+Q₃+Q₄+Q₇, U4+Q₃+Q₄+Q₈, U4+Q₃+Q₄+Q9, U4+Q₃+Q₅+Q₆, U4+Q₃+Q₅+Q₇,U4+Q₃+Q₅+Q₈, U4+Q₃+Q₅+Q₉, U4+Q₃+Q₆+Q₇, U4+Q₃+Q₆+Q₈, U4+Q₃+Q₆+Q9,U4+Q₃+Q₇+Q₈, U4+Q₃+Q₇+Q9, U4+Q₃+Q₈+Q9, U4+Q₄+Q₅+Q₆, U4+Q₄+Q₅+Q₇,U4+Q₄+Q₅+Q₈, U4+Q₄+Q₅+Q₉, U4+Q₄+Q₆+Q₇, U4+Q₄+Q₅+Q₈, U4+Q₄+Q₆+Q₉,U4+Q₄+Q₇+Q₈, U4+Q₄+Q₇+Q₀, U4+Q₄+Q₈+Q₉, U4+Q₅+Q₆+Q₇, U4+Q₅+Q₆+Q₈,U4+Q₅+Q₆+Q₉, U4+Q₅+Q₇+Q₈, U4+Q₅+Q₇+Q₉, U4+Q₅+Q₈+Q₉, U4+Q₆+Q₇+Q₈,U4+Q₆+Q₇+Q₉, U4+Q₆+Q₈+Q₉, U4+Q₁+Q₂+Q₃+Q₄, U4+Q₄+Q₂+Q₃+Q₅,U4+Q₁+Q₂+Q₃+Q₆, U4+Q₁+Q₂+Q₃+Q₇, U4+Q₄+Q₂+Q₃+Q₈, U4+Q₄+Q₂+Q₃+Q9,U4+Q₁+Q₃+Q₄+Q₅, U4+Q₁+Q₃+Q₄+Q₆, U4+Q₄+Q₃+Q₄+Q₇, U4+Q₁+Q₃+Q₄+Q₈,U4+Q₁+Q₃+Q₄+Q₉, U4+Q₄+Q₄+Q₅+Q₆, U4+Q₄+Q₄+Q₅+Q₇, U4+Q₁+Q₄+Q₅+Q₈,U4+Q₁+Q₄+Q₅+Q9, U4+Q₄+Q₅+Q₆+Q₇, U4+Q₁+Q₅+Q₆+Q₈, U4+Q₁+Q₅+Q₆+Q₉,U4+Q₄+Q₆+Q₇+Q₈, U4+Q₄+Q₆+Q7+Q9, U4+Q₁+Q₇+Q₈+Q₉, U4+Q₂+Q₃+Q₄+Q₅,U4+Q₂+Q₃+Q₄+Q₆, U4+Q₂+Q₃+Q₄+Q₇, U4+Q₂+Q₃+Q₄+Q₈, U4+Q₂+Q₃+Q₄+Q₉,U4+Q₂+Q₄+Q₅+Q₆, U4+Q₂+Q₄+Q₅+Q₇, U4+Q₂+Q₄+Q₅+Q₈, U4+Q₂+Q₄+Q₅+Q9,U4+Q₂+Q₅+Q₆+Q₇, U4+Q₂+Q₅+Q₆+Q₈, U4+Q₂+Q₅+Q₆+Q₉, U4+Q₂+Q₆+Q₇+Q₈,U4+Q₂+Q₆+Q₇+Q₉, U4+Q₂+Q₇+Q₈+Q₉, U4+Q₃+Q₄+Q₅+Q₆, U4+Q₃+Q₄+Q₅+Q₇,U4+Q₃+Q₄+Q₅+Q₈, U4+Q₃+Q₄+Q₅+Q9, U4+Q₃+Q₅+Q₆+Q₇, U4+Q₃+Q₅+Q₆+Q₈,U4+Q₃+Q₅+Q₆+Q₉, U4+Q₃+Q₆+Q₇+Q₈, U4+Q₃+Q₆+Q₇+Q₉, U4+Q₃+Q₇+Q₈+Q₉,U4+Q₄+Q₅+Q₆+Q₇, U4+Q₄+Q₅+Q6+Q₈, U4+Q₄+Q₅+Q₆+Q₉, U4+Q₄+Q₆+Q₇+Q₈,U4+Q₄+Q₆+Q₇+Q9, U4+Q₄+Q₇+Q₈+Q₉, U4+Q₅+Q₆+Q₇+Q₈, U4+Q₅+Q₆+Q₇+Q₉,U4+Q₅+Q₇+Q₈+Q₉, U4+Q₁+Q₂+Q₃+Q₄+Q₅, U4+Q₄+Q₂+Q₃+Q₄+Q₆, U4+Q₄+Q₂+Q₃+Q₄+Q₇,U4+Q₁+Q₂+Q₃+Q₄+Q₈, U4+Q₁+Q₂+Q₃+Q₄+Q₉, U4+Q₁+Q₃+Q₄+Q₅+Q₆,U4+Q₁+Q₃+Q₄+Q₅+Q₇, U4+Q₄+Q₃+Q₄+Q₅+Q₈, U4+Q₁+Q₃+Q₄+Q₅+Q9,U4+Q₁+Q₄+Q₅+Q₆+Q₇, U4+Q₁+Q₄+Q₅+Q₆+Q₈, U4+Q₁+Q₄+Q₅+Q₆+Q₉,U4+Q₁+Q₅+Q₆+Q₇+Q₈, U4+Q₁+Q₅+Q₆+Q₇+Q9, U4+Q₁+Q₆+Q₇+Q₈+Q₉,U4+Q₂+Q₃+Q₄+Q₅+Q₆, U4+Q₂+Q₃+Q₄+Q₅+Q₇, U4+Q₂+Q₃+Q₄+Q₅+Q₈,U4+Q₂+Q₃+Q₄+Q₅+Q₉, U4+Q₂+Q₄+Q₅+Q₆+Q₇, U4+Q₂+Q₄+Q₅+Q₆+Q₈,U4+Q₂+Q₄+Q₅+Q₆+Q₉, U4+Q₂+Q₅+Q₆+Q₇+Q₈, U4+Q₂+Q₅+Q₆+Q₇+Q₉,U4+Q₂+Q₆+Q₇+Q₈+Q₉, U4+Q₃+Q₄+Q₅+Q₆+Q₇, U4+Q₃+Q₄+Q₅+Q₆+Q₈,U4+Q₃+Q₄+Q₅+Q₆+Q₉, U4+Q₃+Q₅+Q₆+Q₇+Q₈, U4+Q₃+Q₅+Q₆+Q₇+Q9,U4+Q₃+Q₆+Q₇+Q₈+Q9, U4+Q₄+Q₅+Q₆+Q₇+Q₈, U4+Q₄+Q₅+Q₆+Q₇+Q₉,U4+Q₄+Q₆+Q₇+Q₈+Q₉, U4+Q₅+Q₆+Q₇+Q₈+Q₉, U4+Q₁+Q₂+Q₃+Q₄+Q₅+Q₆,U4+Q₁+Q₂+Q₃+Q₄+Q₆+Q₇, U4+Q₁+Q₂+Q₃+Q₄+Q₅+Q₈, U4+Q₁+Q₂+Q₃+Q₄+Q₅+Q₉,U4+Q₁+Q₃+Q₄+Q₅+Q₆+Q₇, U4+Q₁+Q₃+Q₄+Q₅+Q₆+Q₈, U4+Q₁+Q₃+Q₄+Q₅+Q₆+Q9,U4+Q₁+Q₄+Q₅+Q₆+Q₇+Q₈, U4+Q₁+Q₄+Q₅+Q₆+Q₇+Q₉, U4+Q₁+Q₅+Q₆+Q₇+Q₈+Q₉,U4+Q₂+Q₃+Q₄+Q₅+Q₆+Q₇, U4+Q₂+Q₃+Q₄+Q₅+Q₆+Q₈, U4+Q₂+Q₃+Q₄+Q₅+Q₆+Q₉,U4+Q₂+Q₄+Q₅+Q₆+Q₇+Q₈, U4+Q₂+Q₄+Q₅+Q₆+Q₇+Q₉, U4+Q₂+Q₅+Q₆+Q₇+Q₈+Q₉,U4+Q₃+Q₄+Q₅+Q₆+Q₇+Q₈, U4+Q₃+Q₄+Q₅+Q₆+Q₇+Q₉, U4+Q₃+Q₅+Q₆+Q₇+Q₈+Q9,U4+Q₄+Q₅+Q₆+Q₇+Q₈+Q₉, U4+Q₁+Q₂+Q₃+Q₄+Q₅+Q₆+Q₇, U4+Q₁+Q₂+Q₃+Q₄+Q₅+Q₆+Q₈,U4+Q₁+Q₂+Q₃+Q₄+Q₅+Q₆+Q₉, U4+Q₁+Q₃+Q₄+Q₅+Q₆+Q₇+Q₈,U4+Q₁+Q₃+Q₄+Q₅+Q₆+Q₇+Q₉, U4+Q₁+Q₄+Q₅+Q₆+Q₇+Q₈+Q₉,U4+Q₂+Q₃+Q₄+Q₅+Q₆+Q₇+Q₈, U4+Q₂+Q₃+Q₄+Q₅+Q₆+Q₇+Q₉,U4+Q₂+Q₃+Q₄+Q₅+Q₆+Q₈+Q₉, U4+Q₂+Q₄+Q₅+Q₆+Q7+Q₈+Q9,U4+Q₃+Q₄+Q₅+Q₆+Q₇+Q₈+Q₉, U4+Q₁+Q₂+Q₃+Q₄+Q₅+Q₆+Q7+Q₈,U4+Q₁+Q₂+Q₃+Q₄+Q₅+Q₆+Q₇+Q₉, U4+Q₂+Q₃+Q₄+Q₅+Q₆+Q7+Q₈+Q9, orU4+Q₁+Q₂+Q₃+Q₄+Q₅+Q₆+Q₇+Q₈+Q₉.

In some embodiments of R₉, and independently in combination with anyembodiments of any other relevant substituent classes, R₉ can be—CH₂—OH, —CH₃, —O—CH₃, or —CO—CH₃, preferably —CH₂—OH. Preferably inthese embodiments, R₈ is hydrogen.

In some embodiments of C, and independently in combination with anyembodiments of any other relevant substituent classes, C can be —CH₂—OH,—CH₃, —O—CH₃, or —CO—CH₃, preferably —CH₂—OH. Preferably in theseembodiments, C is in Formula XVI, B is triazole, and 5 is 1.

In some embodiments of R^(d), and independently in combination with anyembodiments of any other relevant substituent classes, R^(d) can be—CH₂—OH, —CH₃, —O—CH₃, or —CO—CH₃, preferably —CH₂—OH. Preferably inthese embodiments, R₁₈, R₁₉, and R₂₀ are N, R₂₁ and R₂₂ are C, and w is1.

Preferred alkynes for use as reagents in 1,3-dipolarcycloadditionreactions include those shown below.

3. Modification Via the Hydroxyl Moiety of the Mannuronate andGuluronate Monomers

Mannuronate and guluronate monomers contain hydroxyl moieties which canserve as a point of covalent modification. In preferred embodiments, thehydroxyl moieties of mannuronate and guluronate residues (1) are reactedas shown in Scheme 3.

Representative Reaction Conditions: i. I-PO(OR₅)₂, pyridine; ii.R₂—CO—R₃, H⁺.

Mannuronate and guluronate residues (A) can be phosphorylated by avariety of methods known in the art, forming covalently modified monomerI. For example, mannuronate and guluronate residues can bephosphorylated by reaction with I—PO(OR₅)₂ in the presence of pyridine(Stowell, J. K, and Widlanski, T. S. Tetrahedron Lett. 1995; 36(11):1825-1826.).

Mannuronate and guluronate residues (A) can also be converted to acyclic acetal using procedures known in the art. For example, a cyclicacetal can be formed by reaction of mannuronate and guluronate residueswith any suitable ketone (R₂—CO—R₃) in acidic conditions.

4. Methods for Preparing Multiply Modified Alginate Polymers

In the case of singularly modified alginate polymers, only a singlereaction or sequence of reactions is performed, introducing one type ofcovalently modified monomer.

In the case of multiply modified alginate polymers, one or morereactions are performed to introduce multiple different types ofcovalently modified monomers into the modified alginate polymer. In someembodiments, multiply modified alginate polymers are prepared usingmultiple sequential synthetic reactions. For example, the multiplymodified alginate polymer shown below can be prepared using twosequential reactions: (1) amidation of mannuronate and guluronatemonomers with methylamine in the presence of CDMT and NMM; and (2)esterification of mannuronate and guluronate residues with ethanol inthe presence of CDMT and NMM.

In alternative embodiments, multiply modified alginate polymers can beprepared using a ‘one-pot’ synthesis. In these embodiments, multiplecovalently modified monomers are introduced into the alginate polymer ina single synthetic step. For example, the multiply modified alginatepolymer shown above can alternatively be prepared in a single syntheticstep by reacting an alginate polymer with methylamine and ethanol in thepresence of CDMT and NMM.

Any type or form of modified alginate, any type or form of alginatemodification, and any type or form of reagent for modifying alginate canbe, independently and in any combination, specifically included orexcluded in any of the disclosed modified alginates, alginatemodifications, reagents for alginate modifications, methods, and kits,and in any context, combination, or use. For example, any type or formof esterification reagent, amidation reagent, click reagent,alkyne-containing reagent, azide-containing reagent, phosphorylatingreagent, and ketone reagent, such as those described above and in theexamples, can be, independently and in any combination, specificallyincluded or excluded from use to modify alginates, and any alginatemodifications and any modified alginates that include or are based onsuch reagents can be, independently and in any combination, specificallyincluded or excluded in any of the disclosed modified alginates,alginate modifications, reagents for alginate modifications, methods,and kits, and in any context, combination, or use.

As another example, any of the reagents described in Table 4 can be,independently and in any combination, specifically included or excludedfrom use to modify alginates, and any alginate modifications and anymodified alginates that include or are based on the reagents describedin Table 4 can be, independently and in any combination, specificallyincluded or excluded in any of the disclosed modified alginates,alginate modifications, reagents for alginate modifications, methods,and kits, and in any context, combination, or use. For example, all ofthe reagents described in Table 4 in combination but excluding reagentY3 can be specifically included or excluded from use to modifyalginates, and any alginate modifications and any modified alginatesthat include or are based on all the reagents described in Table 4 incombination but excluding reagent Y3 can be specifically included orexcluded in any of the disclosed modified alginates, alginatemodifications, reagents for alginate modifications, methods, and kits,and in any context, combination, or use.

As another example, any modified alginate, alginate modification, orreagents for alginate modification described in U.S. Patent ApplicationNo. 20120308650 can be, independently and in any combination,specifically included or excluded. U.S. Patent Application PublicationNo. 20120308650 is hereby incorporated herein by reference in itsentirety, and specifically for its description of modified alginates,alginate modifications, and reagents for alginate modifications. Any ofthe R group substituents for any of the R groups described herein canbe, independently and in any combination, specifically included orexcluded as an option or as the choice for the respective R group.

In some embodiments, at least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 100%of the residues of the alginates are singly modified using the alcohols,alkynes, amines, or combinations thereof, described herein. In someembodiments, at least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%,40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 100% of theresidues of the alginates are multiply modified using the alcohols,alkynes, amines, or combinations thereof, described herein.

D. Purification of Alginates

Commercial alginates are generally obtained from algae. Crude alginatesfrom seaweed contain numerous contaminants, including polyphenols,proteins, and endotoxins (de Vos, P, et al. Biomaterials 2006; 27:5603-5617). The presence of these impurities has been shown to limit thebiocompatibility of implanted alginates.

To optimize the biocompatibility of the chemically modified alginatesdescribed herein, a rigorous purification methodology was developed toeliminate potentially irritating impurities. In preferred embodiments,ultra-pure low viscosity alginate (UPVLVG, FMC Biopolymer) was used as asubstrate for covalent modification. Following each covalentmodification, the modified alginates were filtered through modifiedsilica columns, for example cyano-modified silica columns, aimed atcapturing bulk organic impurities. Finally, after covalent modificationof the alginate polymer is complete, the modified alginates are dialyzedto remove any remaining small-molecule or low molecular weightimpurities. In a preferred method, the modified alginates are dialyzedagainst 10,000 molecular weight cut-off (MWCO) membrane to remove anyremaining small-molecule impurities.

The purity of the modified alginates can be determined by ¹H NMRanalysis. In such an analysis, the ¹H NMR spectra of the modifiedalginate polymer is collected, and peaks corresponding to the modifiedalginate polymer and to any impurities are integrated to determine therelative quantity of each species in the sample. In some embodiments,the purity of the modified alginate polymer, as determined by ¹H NMR, isgreater than 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. Inpreferred embodiments, the purity of the modified alginate polymer, asdetermined by ¹H NMR, is greater than 90%, more preferably greater than95%.

III. Methods of Assessing Biocompatibility

Biocompatibility of the disclosed hydrogel capsules can be assessedusing any suitable techniques. Examples of useful techniques aredescribed below.

A. Assessing Cytotoxicity

The cytotoxicity of the disclosed surface modified hydrogel capsules canbe evaluated on HeLa cells. The surface modified hydrogel capsules andcan be loaded into containers, such as wells of 96-well plates. Thecontainers can be coated with an attachment molecule, such aspoly-L-lysine, if appropriate. Unmodified hydrogel capsule and materialand saline can be loaded into conrainers as controls. HeLa cells canthen be seeded into the wells and incubated for 3 days at 37° C. in ahumidified chamber.

A cell viability assay using3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) canthen be performed, in which the media is aspirated from all containersand an appropriate volume (such as 100 μl for 96-well plate wells) ofDMEM media without phenol red and an appropriate volume (such as 10 μlfor 96-well plate wells) of MTT (5 mg/ml) added to all of thecontainers. The containers can then be incubated for 4 hours at 37° C.in a humidified chamber. After incubation, an appropriate volume (suchas 85 μl for 96-well plate wells) of solution is aspirated and anappropriate volume (such as 100 μl for 96-well plate wells) of DMSO isadded. Purple formazan crystals form during the assay in proportion tothe number of viable HeLa cells present in each container. The contentsof each container can be pipetted up and down to solubilize the formazancrystals prior to measurement. The containers can then be incubated at37° C. for 10 minutes after which the bubbles from agitation areremoved. The plate can be read using a UV/Vis reader at 540 nm with areference at 700 nm. The viability can be normalized to cells seeded incontainers with no hydrogel capsule or material.

B. Assessing Foreign Body Response/Inflammatory Response

Cathepsin activity, which can be detected by fluorescence, can be usedas an indicator of foreign body response (a form of inflammatoryresponse). Mice, such as 8-12 week old male SKH1 mice, can be used toassess foreign body response of the disclosed hydrogel capsules. Afterinjection or implantation of the hydrogel capsule of material, cathepsinactivity can be measured using an in vivo fluorescence assay at varioustimes after injection or implantation. For example, imaging can be takenat 7 days after injection or implantation. 24 hours before in vivofluorescence imaging, 2 nmol of ProSense-680 (VisEn Medical, Woburn,Mass., excitation wavelength 680±10 nm, emission 700±10 nm) can bedissolved in 150 μl sterile PBS and injected into the tail vein of eachmouse to image cathepsin activity.

In vivo fluorescence imaging can be performed with an in vivofluorescence imaging system, such as the IVIS-Spectrum measurementsystem (Xenogen, Hopkinton, Mass.). The can be maintained under inhaledanesthesia during imaging, using, for example, 1-4% isoflurane in 100%oxygen at a flow rate of 2.5 L/min. Images and data can be collected asappropriate for the imaging device being use. As an example, images canbe presented in fluorescence efficiency, which is defined as the ratioof the collected fluorescent intensity to an internal standard ofincident intensity at the selected imaging configuration. Regions ofinterest (ROIs) can be designated around the site of each injection.

Relative cathepsin activity at the point of injection or implantation ofhydrogel capsules can be imaged. The fluorescence intensity can bemeasured and normalized to the fluorescence response measured using theunmodified form of the hydrogel capsule or material in order to quantifythe biocompatibility of the surface modified hydrogel capsules ascompared to unmodified hydrogel capsules.

Inflammatory response can also be assessed by detecting and measuring asuite of cytokines. The cytokine levels can indicate a high or lowinflammatory response. For example, low protein levels of, for example,TNF-α, IL-13, IL-6, G-CSF, GM-CSF, IL-4, CCL2, and CCL4 which are knownmediators of the foreign body response and fibrosis (Rodriguez et al.,J. Biomed. Mater. Res. A 89:152-159 (2009)), can indicate a lack of orlower foreign body response.

C. Assessing Fibrosis

FACS analysis can be performed on retrieved hydrogel capsules andappropriate times after implantation to characterize the differentimmune populations that are recruited to the hydrogel capsules comparedto control hydrogel capsule or material. For example, the presence ofmacrophages, neutrophils, myofibroblasts, of a combination thereof, onhydrogel capsules or at the location of the hydrogel capsules indicate afibrotic response. Cells were tagged with markers for macrophages(CD11b+, CD68+), neutrophils (CD11b+, Ly6 g+), or myofibroblasts (SMA).FACS was used to determine the levels of these fibrosis-associated celltypes in proximity to the hydrogel capsule or material.

D. qPCR Analysis of Innate Immune and Firbrosis Markers

Total RNA is isolated from a source, such as capsules or productsretrieved from an animal after implantation for a period of time, bysnap freezing in liquid nitrogen immediately following excision, using,for example, TRIzol (Invitrogen; Carlsbad, Calif.) according to themanufacturer's instructions. In addition, to help ensure complete tissuedisruption, strong mechanical disruption with a Polytron homogenizer canalso be employed. By this process, gene expression signatures areproportional and representative of the entire cell population present onand/or around retrieved materials. Before reverse transcription using,for example, the High Capacity cDNA Reverse Transcription kit (Cat.#4368814; Applied Biosystems, Foster City, Calif.), all samples arefirst normalized for comparison by loading the same input total RNA in aset volume (1 μg total RNA in a volume of 20 μl, for example) for eachsample. cDNA (4.8 μl; 1:20 dilution in a total volume of 16 μl, forexample), including a nucleic acid stain, such as SYBR Green, and PCRprimers, is amplified by qPCR with the following appropriate primers(such as the primers shown in Table 1). These primers (Table 1) weredesigned using Primer Express software (Applied Biosystems, Carlsbad,Calif., USA) and evaluated using LaserGene software (DNAStar, Madison,Wis., USA) to ensure either mouse or rat (host)-specificity. Otherprimers can be designed by similar or equivalent analysis. Samples areincubated, for example, at 95° C. for 10 min followed by 40 cycles of95° C. for 15 sec and 60° C. for 1 min in, for example, an ABI PRISM7900HT Sequence Detection System (Applied Biosystems). Results areanalyzed using a suitable method, such as the comparative CT (DDCT)method as described by Applied Biosystems. Results are presented, forexample, as relative RNA levels compared to the RNA expression in eithermock-implanted control cell samples (peripheral intraperitoneal fattissue, or free floating intraperitoneal lavage cells) afternormalization to the β-actin RNA content of each sample.

TABLE 1  Mouse (m) or rat (r)-specific (host) forwardand reverse primer sets used for qPCR analysisof RNA levels. Gene names are also shown in parentheses.Primers (5′to 3′): Gene Sense & Antisense Mouse Forward: Collagen5′-CATGTTCAGCTTTGTGGACCT-3′ 1a1 (SEQ ID NO: 1) (mColla1) Reverse:5′-GCAGCTGACTTCAGGGATGT-3′ (SEQ ID NO: 2) Mouse Froward: Collagen5′-GCAGGTTCACCTACTCTGTCCT-3′ 1a2 (SEQ ID NO: 3) (mColla2) Reverse:5′-CTTGCCCCATTCATTTGTCT-3′ (SEQ ID NO: 4) Mouse Forward: Alpha5′-CGCTTCCGCTGCCCAGAGACT-3′ Smooth (SEQ ID NO: 5) Muscle Reverse: actin5′-TATAGGTGGTTTCGTGGATGCCCGCT-3′ (mActa2) (SEQ ID NO: 6) Mouse Forward:Myeloid 5′-CCAAGAGAATGCAAAAGGCTTT-3′ cell (SEQ ID NO: 7) Marker Reverse:CD11b 5′-GGGGGGCTGCAACAACCACA-3′ (mItgam) (SEQ ID NO: 8) Mouse Forward:Macrophage 5′-GCCCGAGTACAGTCTACCTGG-3′ Marker (SEQ ID NO: 9) CD68Reverse: (mCD68) 5′-AGAGATGAATTCTGCGCCAT-3′ (SEQ ID NO: 10) MouseForward: neutrophil 5′-TGCCCCTTCTCTGATGGATT-3′ Marker (SEQ ID NO: 11)Gr1 Reverse: (mLy6g) 5′-TGCTCTTGACTTGCTTCTGTGA-3′ (SEQ ID NO: 12) MouseForward: β-actin 5′-GCTTCTTTGCAGCTCCTTCGTT-3′ (mActB) (SEQ ID NO: 13)Reverse: 5′-CGGAGCCGTTCTCGACGACC-3′ (SEQ ID NO: 14) Rat Forward:Collagen 5′-CATGTTCAGCTTTGTGGACCT-3′ 1a1 (SEQ ID NO: 15) (rColla1)Reverse: 5′-GCAGCTGACTTCAGGGATGT-3′ (SEQ ID NO: 16) Rat Forward:Collagen 5′-CCTGGCTCTCGAGGTGAAC-3′ 1a2 (SEQ ID NO: 17) (rColla2)Reverse: 5′-CAATGCCCAGAGGACCAG-3′ (SEQ ID NO: 18) Rat Forward: Alpha5′-TGCCATGTATGTGGCTATTCA-3′ Smooth (SEQ ID NO: 19) Muscle Reverse: actin5′-ACCAGTTGTACGTCCAGAAGC-3′ (rActa2) (SEQ ID NO: 20) Rat Forward: Pdx15′-CTCTCGTGCCATGTGAACC-3′ (rPdx1) (SEQ ID NO: 21) Reverse:5′-TTCTCTAAATTGGTCCCAGGAA-3′ (SEQ ID NO: 22) Rat Forward: β-actin5′-ACCTTCTTGCAGCTCCTCCGTC-3′ (rActB) (SEQ ID NO: 23) Reverse:5′-CGGAGCCGTTGTCGACGACG-3′ (SEQ ID NO: 24)

E. FACS Analysis

Single-cell suspensions from capsules or products freshly excised froman animal after implantation for a period of time (or of tissues freshlyexcised from an animal) are prepared using, for example, a gentleMACSDissociator (Miltenyi Biotec, Auburn, Calif.) according to themanufacturer's protocol. Single-cell suspensions are prepared in apassive PEB dissociation buffer (IX PBS, pH 7.2, 0.5% BSA, and 2 mMEDTA) and suspensions are passed through 70 μm filters (for example,Cat. #22363548, Fisher Scientific, Pittsburgh, Pa.). This processremoves the majority of cells adhered to the surface (>90%). Thesingle-cell populations thus derived are then subjected to red bloodcell lysis with 5 ml of 1×RBC lysis buffer (Cat. #00-4333, eBioscience,San Diego, Calif., USA) for 5 min at 4° C. The reaction is terminated bythe addition of 20 ml of sterile IX PBS. The cells remaining arecentrifuged at 300-400 g at 4° C., and resuspended in a minimal volume(˜50 μl) of, for example, eBioscience Staining Buffer (Cat. #00-4222)for antibody incubation. All samples are then co-stained in the dark for25 min at 4° C. with fluorescently tagged monoclonal antibodies specificfor the appropriate cell markers, such as for CD68 (for example,CD68-Alexa647, Clone FA-11, Cat. #11-5931, BioLegend at 1 μl (0.5 μg)per sample), Ly-6G (Gr-1) (for example, Ly-6G-Alexa-647, Clone RB6-8C5,Cat. #108418, BioLegend at 1 μl (0.5 μg) per sample), or CD11b (forexample, CD11b-Alexa-488, Clone M1/70, Cat. #101217, BioLegend at 1 μl(0.2 μg) per sample). Two ml of, for example, eBioscience Flow CytometryStaining Buffer (Cat. #00-4222, eBioscience) is then added, and thesamples are centrifuged at 400-500 g for 5 min at 4° C. Supernatants areremoved by aspiration, and this wash step is repeated two more timeswith staining buffer. Following the third wash, each sample isresuspended in 500 μl of, for example, FlowCytometry Staining Buffer andrun through a 40 μm filter (for example, Cat. #22363547, FisherScientific) for eventual FACS analysis using a FACS machine (forexample, BD FACSCalibur (cat. #342975), BD Biosciences, San Jose,Calif., USA). For proper background and laser intensity settings,unstained, single antibody, and IgG (labeled with, for example,Alexa-488 or Alexa-647, BioLegend) controls can also be run.

F. Fabrication of Alginate Hydrogel Capsules and Cell Encapsulation

All buffers are sterilized by autoclave and alginate solutions aresterilized by filtration through a 0.2 um filter. After solutions aresterilized, aseptic processing is implemented by performing capsuleformation in a type II class A2 biosafety cabinet to maintain sterilityof manufactured microcapsules/spheres for subsequent implantation. Thehydrogel capsules are formed by the following protocol.

To solubilize alginates, SLG20 (NovaMatrix, Sandvika, Norway) isdissolved at 1.4% weight to volume in 0.8% saline. TMTD alginate isinitially dissolved at 5% weight to volume in 0.8% saline, and thenblended with 3% weight to volume SLG100 (also dissolved in 0.8% saline)at a volume ratio of 80% TMTD alginate to 20% SLG100.

Forming different sized capsules: for 300 μm diameter capsules, a 30gauge blunt tipped needle (SAI Infusion Technologies) is used with avoltage of 7-8 kV. For 500 μm diameter capsules, a 25 gauge blunt tippedneedle (SAI Infusion Technologies) is used with a voltage of 5-7 kV. For1.5 mm capsules, an 18 gauge blunt tipped needle (SAI InfusionTechnologies) is used with a voltage of 5-7 kV.

Cells, such as human islet cells or cultured human cells, are used forencapsulation. Immediately prior to encapsulation, the cultured humancell clusters are centrifuged at 1,400 rpm for 1 minute and washed withCa-free Krebs-Henseleit (KH) Buffer (4.7 mM KCl, 25 mM HEPES, 1.2 mMKH₂PO₄, 1.2 mM MgSO₄×7H₂O, 135 mM NaCl, pH≈7.4, ≈290 mOsm). Afterwashing, the human cells are centrifuged again and all supernatant isaspirated. The human cell pellet is then re-suspended in the SLG20 orTMTD alginate solutions at cluster densities of 1,000, 250, and 100clusters per 0.5 ml alginate solution.

An electrostatic droplet generator is set up as follows: an ES series0-100 KV, 20 Watt high voltage power generator (Gamma ES series, GammaHigh Voltage Research, FL, USA) is connected to the top and bottom of ablunt tipped needle (SAI Infusion Technologies, IL, USA). This needle isattached to a 5 mL lure lock syringe (BD, NJ, USA) which is clipped to asyringe pump (Pump 11 Pico Plus, Harvard Apparatus, MA, USA) that isoriented vertically. The syringe pump pumps alginate out into a glassdish containing a 20 mM barium 5% mannitol solution (Sigma Aldrich, MO,USA). The settings of the PicoPlus syringe pump are 12.06 mm diameterand 0.2 mL/min flow rate. Immediately after crosslinking, theencapsulated human cell clusters are washed 4 times with 50 mL of CMRLMmedia and cultured overnight in a spinner flask at 37° C. prior totransplantation. Due to an inevitable loss of human cell clusters duringthe encapsulation process, the total number of encapsulated clusters arerecounted post-encapsulation.

G. Analysis of Cell Viability of Encapsulated Cells and/or ProteinSecreted from Encapsulated Cells

Encapsulated cells are added in 3 ml of fresh medium to each well of asix-well tissue-culture polystyrene plate. Culturing of encapsulatedcells is maintained for four days. Afterwards, supernatant samples canbe collected and frozen at −20° C. for future analysis, such as byWestern blot or ELISA. Encapsulated cells are collected into new plates.Both encapsulated cells are washed in HEPES buffer and subjected tolive-dead fluorescent staining (Invitrogen) for viability assessment.The proportion of encapsulated cells that are viable (live) can becalculated. The secretion level of one or more proteins of interest,such as insulin form islet cels or a protein of interest secreted by arecombinant cell, can be assessed by analyzing the supernatant byWestern blot or ELISA. The level of secretion can be assessed by, forexample, raw level, normalized level (normalized to the level of ahousekeeping secreted protein, for example), or either of these comparedto the level measured form control cells.

H. Insulin Secretion Analysis

Encapsulated islet cell insulin responses are assessed by loadingcapsules or product containing encapsulated islet cells into amicrofluidic device modified for encapsulated islets (Nourmohammadzadehet al., Analytical Chem. 85:11240-11249 (2013)). The encapsulated isletcells can be, for example, newly encapsulated or retrieved afterimplantation into a subject, such as a mouse. Perifusate samples arecollected every minute (500 μL/min) by an automated fraction collector(Gilson, model 203B, WI, USA). Insulin concentrations are quantifiedevery other minute using, for example, a chemiluminescent insulin ELISA(Alpco, NH, USA). The following perifusion protocol is used: (1) KRB2(0-20 min); (2) 20 mM glucose or 30 mM KCl (20-55 min); (3) KRB2 (55-100min). An appropriate measure of the secreted insulin can be calculated.For example, the area under the curve for each insulin curve can becalculated in order to statistically compare groups using one-way ANOVA(p<0.05 as significant).

Biological and temporal characteristics of the disclosed capsules can beassessed by any suitable analysis. For example, the length of time acapsule implanted into a subject remains acceptably free of fibroticeffects, produces a desired effect, maintains encapsulated cellviability, or combinations thereof can be assessed. Analogously, thesuitability of surface modifications for facilitating desirablebiological and temporal characteristics of the disclosed capsules can beassessed in similar ways. In some embodiments, a capsule with surfacemodifications as described herein, if implanted into and retrieved froman immunocompetent animal, such as a C57BL/6J mouse, as describedherein, can have one or more of the following properties:

(a) expression of one or more immune and fibrosis markers on the capsulewill be less than 3-fold higher, 2.5-fold higher, 2-fold higher, or1.5-fold higher than in untreated control tissue at least 14 days, 30days, 60 days, 120 days, 240 days, or 360 days after implantation intothe immunocompetent animal as determined by, for example, Western blotanalysis, ELISA, or qPCR analysis as known in the art or as describedherein;

(b) expression of one or more immune and fibrosis markers on the capsulewill be less than 3-fold higher, 2.5-fold higher, 2-fold higher, or1.5-fold higher than in untreated control tissue at least 14 days, 30days, 60 days, 120 days, 240 days, or 360 days after implantation intothe immunocompetent animal as determined by, for example, Western blotanalysis, ELISA, or qPCR analysis as known in the art or as describedherein;

(c) the cell population of one or more immune- and fibrosis-associatedcells on the capsule will be less than 20%, 18%, 15%, 12%, 10%, of 5% ofthe cell population observed for a control similar capsule lacking thesurface modification at least 14 days, 30 days, 60 days, 120 days, 240days, or 360 days after implantation into the immunocompetent animal asdetermined by, for example, FACS analysis or ELISA as known in the artor as described herein;

(d) expression of a cell viability marker from cells encapsulated in thecapsule will be more than 2-fold higher, 3-fold higher, 3.5-fold higher,4-fold higher, 5-fold higher, or 10-fold higher observed for similarencapsulated cells comprised in a control similar capsule lacking thesurface modification at least 14 days, 30 days, 60 days, 120 days, 240days, or 360 days after implantation into the immunocompetent animal asdetermined by, for example, FACS analysis, Western blot analysis, ELISA,histology, or qPCR analysis as known in the art or as described herein;

(e) secretion of a protein of interest from cells encapsulated in thecapsule will be detectable at least 14 days, 30 days, 60 days, 120 days,240 days, or 360 days after implantation into the immunocompetent animalas determined by, for example, Western blot analysis or ELISA as knownin the art or as described herein;

(f) secretion of insulin from islet cells encapsulated in the capsulewill be detectable at least 14 days, 30 days, 60 days, 120 days, 240days, or 360 days after implantation into the immunocompetent animal asdetermined by, for example, Western blot analysis or ELISA as known inthe art or as described herein; and

(g) at least 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10% of the cellsencapsulated in the capsule will be viable for at least 14 days, 30days, 60 days, 120 days, 240 days, or 360 days after implantation intothe immunocompetent animal as determined by, for example, cell viabilityanalysis as known in the art or as described herein.

The compounds used for the surface modification can be assessed forfacilitating desireable biological and temporal characteristics oncapsules by, for example, fabricating aliginate capsules modified withthe compound to encapsulate human islet cells, implanting the alginatecapsules into and retrieving the alginate capsules from a C57BL/6J mouseas described herein, and assessing a suitable property of the retrievedalginate capsules. In some embodiments, the retrieved alginate capsulescan have one or more of the following properties:

(a) expression of an islet cell viability marker from the alginatecapsules will be more than 2-fold higher, 3-fold higher, 3.5-foldhigher, 4-fold higher, 5-fold higher, or 10-fold higher observed for acontrol similar alginate capsule lacking the surface modification atleast 14 days, 30 days, 60 days, 120 days, 240 days, or 360 days afterimplantation into the immunocompetent animal as determined by, forexample, FACS analysis, Western blot analysis, ELISA, histology, or qPCRanalysis as known in the art or as described herein;

(b) secretion of insulin from the islet cells encapsulated in thealginate capsule will be detectable at least 14 days, 30 days, 60 days,120 days, 240 days, or 360 days after implantation into theimmunocompetent animal as determined by, for example, Western blotanalysis or ELISA as known in the art or as described herein;

(c) expression of one or more immune and fibrosis markers on thealginate capsule will be less than 3-fold higher, 2.5-fold higher,2-fold higher, or 1.5-fold higher than in untreated control tissue atleast 14 days, 30 days, 60 days, 120 days, 240 days, or 360 days afterimplantation into the immunocompetent animal as determined by, forexample, Western blot analysis, ELISA, or qPCR analysis as known in theart or as described herein;

(b) expression of one or more immune and fibrosis markers on thealginate capsule will be less than 3-fold higher, 2.5-fold higher,2-fold higher, or 1.5-fold higher than in untreated control tissue atleast 14 days, 30 days, 60 days, 120 days, 240 days, or 360 days afterimplantation into the immunocompetent animal as determined by, forexample, Western blot analysis, ELISA, or qPCR analysis as known in theart or as described herein;

(c) the cell population of one or more immune- and fibrosis-associatedcells on the alginate capsule will be less than 20%, 18%, 15%, 12%, 10%,of 5% of the cell population observed for a control similar capsulelacking the surface modification at least 14 days, 30 days, 60 days, 120days, 240 days, or 360 days after implantation into the immunocompetentanimal as determined by, for example, FACS analysis or ELISA as known inthe art or as described herein;

(d) expression of a cell viability marker from the islet cellsencapsulated in the alginate capsule will be more than 2-fold higher,3-fold higher, 3.5-fold higher, 4-fold higher, 5-fold higher, or 10-foldhigher observed for similar encapsulated cells comprised in a controlsimilar capsule lacking the surface modification at least 14 days, 30days, 60 days, 120 days, 240 days, or 360 days after implantation intothe immunocompetent animal as determined by, for example, FACS analysis,Western blot analysis, ELISA, histology, or qPCR analysis as known inthe art or as described herein;

(e) secretion of a protein of interest from the islet cells encapsulatedin the alginate capsule will be detectable at least 14 days, 30 days, 60days, 120 days, 240 days, or 360 days after implantation into theimmunocompetent animal as determined by, for example, Western blotanalysis or ELISA as known in the art or as described herein; and

(g) at least 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10% of the theislet cells encapsulated in the capsule will be viable for at least 14days, 30 days, 60 days, 120 days, 240 days, or 360 days afterimplantation into the immunocompetent animal as determined by, forexample, cell viability analysis as known in the art or as describedherein.

In some embodiments of the capsule, a similar capsule, if implanted intoand retrieved from a C57BL/6J mouse as described herein has thefollowing property: expression of one or more immune and fibrosismarkers on the capsule will be less than 3-fold higher than in untreatedcontrol tissue at least 30 days after implantation into the C57BL/6Jmouse as determined by, for example, Western blot analysis, ELISA, orqPCR analysis as known in the art or as described herein.

In some embodiments of the capsule, a similar capsule, if implanted intoand retrieved from a C57BL/6J mouse as described herein has thefollowing property: the cell population of one or more immune- andfibrosis-associated cells on the capsule will be less than 20% of thecell population observed for an identical capsule lacking the surfacemodification at least 14 days after implantation into the C57BL/6J mouseas determined by, for example, FACS analysis, Western blot analysis,ELISA, or histology as known in the art or as described herein.

In some embodiments of the capsule, alginate capsules, (a) fabricated asdescribed herein to encapsulate human islet cells and (b) having thesurface modification of the capsule on the outer surface of alginatecapsules at a similar density as on the surface of the capsule, providesencapsulated human islet cells that, if implanted into and retrievedfrom a C57BL/6J mouse as described herein has the following property:expression of an islet cell viability marker from the alginate capsuleswill be more than 2-fold higher observed for an identical alginatecapsule lacking the surface modification at least 30 days afterimplantation into the C57BL/6J mouse as determined by, for example, FACSanalysis, Western blot analysis, ELISA, histology, or qPCR analysis asknown in the art or as described herein.

In some embodiments of the capsule, alginate capsules, (a) fabricated asdescribed herein to encapsulate human islet cells and (b) having thesurface modification of the capsule on the outer surface of alginatecapsules at a similar density as on the surface of the capsule, providesencapsulated human islet cells that, if implanted into and retrievedfrom a C57BL/6J mouse as described herein has the following property:the encapsulated islet cells will be able to secrete detectable levelsof insulin at least 30 days after implantation into the C57BL/6J mouseas determined by, for example, Western blot analysis or ELISA as knownin the art or as described herein.

In some embodiments of the capsule, the capsule includes encapsulatedcells, where the encapsulated cells, if implanted, via implantation ofthe capsule, into and retrieved from a C57BL/6J mouse as describedherein has the following property: expression of a cell viability markerfrom the encapsulated cells will be more than 2-fold higher observed forsimilar encapsulated cells included in an identical capsule lacking thesurface modification at least 30 days after implantation into theC57BL/6J mouse as determined by, for example, FACS analysis, Westernblot analysis, ELISA, histology or qPCR analysis as known in the art oras described herein.

In some embodiments of the capsule, the capsule includes encapsulatedcells expressing and secreting a protein of interest, where theencapsulated cells, if implanted, via implantation of the capsule, intoand retrieved from a C57BL/6J mouse as described herein has thefollowing property: the encapsulated islet cells will be able to secretedetectable levels of the protein of interest at least 30 days afterimplantation into the C57BL/6J mouse as determined by, for example,Western blot analysis or ELISA as known in the art or as describedherein.

For testing of a capsule of interest, suitable capsules can be, forexample, a capsule identical to the capsule of interest, a correspondingcapsule to the capsule of interest, a similar capsule to the capsule ofinterest, a capsule having identical surface modification as the capsuleof interest, a capsule having a corresponding surface modification asthe capsule of interest, or a capsule having a similar surfacemodification as the capsule of interest. For testing of a compound,chemical modification, or surface modification of interest, suitablecapsules can be, for example, a capsule surface modified with thecompound of interest, a capsule with the chemical modification ofinterest, or a capsule with the surface modification of interest.

IV. Biological Materials

Biological material for encapsulation in the disclosed alginates can beany biological substance. For example, the biological material can betissue, cells, biological micromolecules, or biological macromolecules.Examples of biological macromolecules include nucleotides, amino acids,cofactors, and hormones. Examples of biological macromolecules includenucleic acids, polypeptides, proteins, and polysaccharides. Examples ofproteins include enzymes, receptors, secretory proteins, structuralproteins, signaling proteins, hormones, and ligands. Any class, type,form, or particular biological material can be used together with anyother classes, types, forms, or particular biological materials.

A. Cells

The cell type chosen for encapsulation in the disclosed compositionsdepends on the desired therapeutic effect. The cells may be from thepatient (autologous cells), from another donor of the same species(allogeneic cells), or from another species (xenogeneic). Xenogeneiccells are easily accessible, but the potential for rejection and thedanger of possible transmission of viruses to the patient restrictstheir clinical application. Any of these types of cells can be fromnatural sources, stem cells, derived cells, or genetically engineeredcell.

In some embodiments, the cells secrete a therapeutically effectivesubstance, such as a protein or nucleic acid. In some embodiments, thecells produce a metabolic product. In some embodiments, the cellsmetabolize toxic substances. In some embodiments, the cells formstructural tissues, such as skin, bone, cartilage, blood vessels, ormuscle. In some embodiments, the cells are natural, such as islet cellsthat naturally secrete insulin, or hepatocytes that naturally detoxify.In some embodiments, the cells are genetically engineered to express aheterologous protein or nucleic acid and/or overexpress an endogenousprotein or nucleic acid.

Types of cells for encapsulation in the disclosed compositions includecells from natural sources, such as cells from xenotissue, cells from acadaver, and primary cells; stem cells, such as embryonic stem cells,mesenchymal stem cells, and induced pluripotent stem cells; derivedcells, such as cells derived from stem cells, cells from a cell line,reprogrammed cells, reprogrammed stem cells, and cells derived fromreprogrammed stem cells; and genetically engineered cells, such as cellsgenetically engineered to express a protein or nucleic acid, cellsgenetically engineered to produce a metabolic product, and cellsgenetically engineered to metabolize toxic substances.

Types of cells for encapsulation in the disclosed compositions includehepatocytes, islet cells, parathyroid cells, endocrine cells, cells ofintestinal origin, cells derived from the kidney, and other cells actingprimarily to synthesize and secret, or to metabolize materials. Apreferred cell type is a pancreatic islet cell or otherinsulin-producing cell. Hormone-producing cells can produce one or morehormones, such as insulin, parathyroid hormone, anti-diuretic hormone,oxytocin, growth hormone, prolactin, thyroid stimulating hormone,adrenocorticotropic hormone, follicle-stimulating hormone, lutenizinghormone, thyroxine, calcitonin, aldosterone, cortisol, epinephrine,glucagon, estrogen, progesterone, and testosterone. Geneticallyengineered cells are also suitable for encapsulation according to thedisclosed methods. In some embodiments, the cells are engineered toproduce one or more hormones, such as insulin, parathyroid hormone,anti-diuretic hormone, oxytocin, growth hormone, prolactin, thyroidstimulating hormone, adrenocorticotropic hormone, follicle-stimulatinghormone, lutenizing hormone, thyroxine, calcitonin, aldosterone,cortisol, epinephrine, glucagon, estrogen, progesterone, andtestosterone. In some embodiments, the cells are engineered to secreteblood clotting factors (e.g., for hemophilia treatment) or to secretegrowth hormones. In some embodiments, the cells are contained in naturalor bioengineered tissue. For example, the cells for encapsulation are insome embodiments a bioartificial renal glomerulus. In some embodiments,the cells are suitable for transplantation into the central nervoussystem for treatment of neurodegenerative disease.

Cells can be obtained directly from a donor, from cell culture of cellsfrom a donor, or from established cell culture lines. In the preferredembodiments, cells are obtained directly from a donor, washed andimplanted directly in combination with the polymeric material. The cellsare cultured using techniques known to those skilled in the art oftissue culture.

Cell viability can be assessed using standard techniques, such ashistology and fluorescent microscopy. The function of the implantedcells can be determined using a combination of these techniques andfunctional assays. For example, in the case of hepatocytes, in vivoliver function studies can be performed by placing a cannula into therecipient's common bile duct. Bile can then be collected in increments.Bile pigments can be analyzed by high pressure liquid chromatographylooking for underivatized tetrapyrroles or by thin layer chromatographyafter being converted to azodipyrroles by reaction with diazotizedazodipyrroles ethylanthranilate either with or without treatment withP-glucuronidase. Diconjugated and monoconjugated bilirubin can also bedetermined by thin layer chromatography after alkalinemethanolysis ofconjugated bile pigments. In general, as the number of functioningtransplanted hepatocytes increases, the levels of conjugated bilirubinwill increase. Simple liver function tests can also be done on bloodsamples, such as albumin production. Analogous organ function studiescan be conducted using techniques known to those skilled in the art, asrequired to determine the extent of cell function after implantation.For example, pancreatic islet cells and other insulin-producing cellscan be implanted to achieve glucose regulation by appropriate secretionof insulin. Other endocrine tissues and cells can also be implanted.

The site, or sites, where cells are to be implanted is determined basedon individual need, as is the requisite number of cells. For cellsreplacing or supplementing organ or gland function (for example,hepatocytes or islet cells), the mixture can be injected into themesentery, subcutaneous tissue, retroperitoneum, properitoneal space,and intramuscular space.

The amount and density of cells encapsulated in the disclosedcompositions, such as capsules and microcapsules, will vary depending onthe choice of cell, hydrogel, and site of implantation. In someembodiments, the single cells are present in the hydrogel at aconcentration of 0.1×10⁶ to 4×10⁶ cells/ml, preferred 0.5×10⁶ to 2×10⁶cells/ml. In other embodiments, the cells are present as cellaggregates. For example, islet cell aggregates (or whole islets)preferably contain about 1500-2000 cells for each aggregate of 150 μmdiameter, which is defined as one islet equivalent (IE). Therefore, insome embodiments, islet cells are present at a concentration of100-10000 IE/ml, preferably 200-3,000 IE/ml, more preferably 500-1500IE/ml.

1. Islet Cells and Other Insulin-Producing Cells

In preferred embodiments, the disclosed compositions contain islet cellsor other insulin-producing cells. Methods of isolating pancreatic isletcells are known in the art. Field et al., Transplantation 61:1554(1996); Linetsky et al., Diabetes 46:1120 (1997). Fresh pancreatictissue can be divided by mincing, teasing, comminution and/orcollagenase digestion. The islets can then be isolated fromcontaminating cells and materials by washing, filtering, centrifuging orpicking procedures. Methods and apparatus for isolating and purifyingislet cells are described in U.S. Pat. No. 5,447,863 to Langley, U.S.Pat. No. 5,322,790 to Scharp et al., U.S. Pat. No. 5,273,904 to Langley,and U.S. Pat. No. 4,868,121 to Scharp et al. The isolated pancreaticcells may optionally be cultured prior to microencapsulation, using anysuitable method of culturing islet cells as is known in the art. Seee.g., U.S. Pat. No. 5,821,121 to Brothers. Isolated cells may becultured in a medium under conditions that helps to eliminate antigeniccomponents. Insulin-producing cells can also be derived from stem cellsand cell lines and can be cells genetically engineered to produceinsulin.

2. Genetically Engineered Cells

In some embodiments, the disclosed compositions contain cellsgenetically engineered to produce a protein or nucleic acid (e.g., atherapeutic protein or nucleic acid). In these embodiments, the cell canbe, for example, a stem cell (e.g., pluripotent), a progenitor cell(e.g., multipotent or oligopotent), or a terminally differentiated cell(i.e., unipotent). Any of the disclosed cell types can be geneticallyengineered. The cell can be engineered, for example, to contain anucleic acid encoding, for example, a polynucleotide such miRNA or RNAior a polynucleotide encoding a protein. The nucleic acid can be, forexample, integrated into the cells genomic DNA for stable expression orcan be, for example, in an expression vector (e.g., plasmid DNA). Thepolynucleotide or protein can be selected based on the disease to betreated (or effect to be achieved) and the site of transplantation orimplantation. In some embodiments, the polynucleotide or protein isanti-neoplastic. In other embodiments, the polynucleotide or protein isa hormone, growth factor, or enzyme.

B. Hormones

Hormones to be included in the disclosed capsules or, most preferably,produced from cells encapsulated in the disclosed capsules can be anyhormone of interest.

Examples of endocrine hormones include Anti-diuretic Hormone (ADH),which is produced by the posterior pituitary, targets the kidneys, andaffects water balance and blood pressure; Oxytocin, which is produced bythe posterior pituitary, targets the uterus, breasts, and stimulatesuterine contractions and milk secretion; Growth Hormone (GH), which isproduced by the anterior pituitary, targets the body cells, bones,muscles, and affects growth and development; Prolactin, which isproduced by the anterior pituitary, targets the breasts, and maintainsmilk secretions; Thyroid Stimulating Hormone (TSH), which is produced bythe anterior pituitary, targets the thyroid, and regulates thyroidhormones; Adrenocorticotropic Hormone (ACTH), which is produced by theanterior pituitary, targets the adrenal cortex, and regulates adrenalcortex hormones; Follicle-Stimulating Hormone (FSH), which is producedby the anterior pituitary, targets the ovaries/testes, and stimulatesegg and sperm production; Lutenizing Hormone (LH), which is produced bythe anterior pituitary, targets the ovaries/testes, and stimulatesovulation and sex hormone release; Thyroxine, which is produced by thethyroid, targets the body cells, and regulates metabolism; Calcitonin,which is produced by the thyroid, targets the adrenal cortex, and lowersblood calcium; Parathyroid Hormone, which is produced by theparathyroid, targets the bone matrix, and raises blood calcium;Aldosterone, which is produced by the adrenal cortex, targets thekidney, and regulates water balance; Cortisol, which is produced by theadrenal cortex, targets the body cells, and weakens immune system andstress responses; Epinephrine, which is produced by the adrenal medulla,targets the heart, lungs, liver, and body cells, and affects primary“fight or flight” responses; Glucagon, which is produced by thepancreas, targets the liver body, and raises blood glucose level;Insulin, which is produced by the pancreas, targets body cells, andlowers blood glucose level; Estrogen, which is produced by the ovaries,targets the reproductive system, and affects puberty, menstrual, anddevelopment of gonads; Progesterone, which is produced by the ovaries,targets the reproductive system, and affects puberty, menstrual cycle,and development of gonads; and Testosterone, which is produced by theadrenal gland, testes, targets the reproductive system, and affectspuberty, development of gonads, and sperm.

V. Assays for the Characterization of Modified Alginate Polymers

The covalent modification of alginate polymers alters the physiochemicalproperties and biological compatibility of the alginate polymer.

In some embodiments, a hydrogel formation assay is used to quantify thestability of hydrogels formed from alginates or modified alginates. Inpreferred embodiments, the hydrogel formation assay is used as ascreening tool to identify modified alginates capable of forming stablehydrogels.

In vivo assays can be useful to characterize the biocompatibility ofmodified alginate polymers. In some embodiments, the high throughput invivo biocompatibility assay described herein is used to identifymodified alginates which induce a lower foreign body response thanunmodified alginate.

Further described herein is an in vivo method for quantifying thebiocompatibility of modified alginates.

The assays can be used to assess the suitability and biocompatibility ofboth modified and unmodified alginates for certain applications.

A. High Throughput Hydrogel Formation Assay

Covalent modification of the alginates affects the physical propertiesof the alginate, including the ability of the alginate to form hydrogelssuitable for the encapsulation of cells and biomolecules.

The gel-forming assay exploits the ability of hydrogels to trapfluorescent compounds, and differentially retain the fluorophores uponwashing based on the stability of the hydrogel. In this assay, ahydrogel formed by ionically crosslinking a candidate modified alginatein aqueous solution containing a dissolved fluorophore. A variety offluorophores can be used in this assay. In preferred embodiments, thefluorophores possess emission maxima between 480 and 750 nm. Inpreferred embodiments, the fluorophore is a rhodamine dye possessing anemission maximum between 550 and 600 nm.

After crosslinking, the hydrogel is repeatedly washed with water.Candidate modified alginates which do not efficiently crosslink arewashed away along with any fluorophore present. Modified alginates whichefficiently crosslink retain the fluorophore during washes. Accordingly,by measuring the fluorescence of modified alginate hydrogels afterwashing, modified alginates capable of forming stable hydrogels can bereadily identified.

In some embodiments, the relative fluorescence intensity values measuredfor a modified alginate are compared relative to fluorescence levelsmeasured for the negative control and unmodified alginate to determineif the modified alginate is capable of forming hydrogels. In alternativeembodiments, the hydrogel formation assay described herein is used toquantify the stability of hydrogels formed from alginates or modifiedalginates. In these embodiments, the fluorescence intensity measured fora modified alginate is used to indicate the stability of the hydrogelformed by the alginate.

In preferred embodiments, the modified alginate polymer forms hydrogelssuch that the fluorescence intensity measured using the high throughputhydrogel formation assay described herein is greater than 10,000,15,000, 20,000, 25,000, 30,000, 35,000, 40,000, 45,000, 50,000, or55,000. In preferred embodiments, the modified alginate polymer formshydrogels such that the fluorescence intensity measured using the highthroughput hydrogel formation assay described herein is greater than15,000. In preferred embodiments, the modified alginate polymer formshydrogels such that the fluorescence intensity measured using the highthroughput hydrogel formation assay described herein is between 15,000and 55,000, more preferably between 25,000 and 55,000.

B. High Throughput In Vivo Biocompatibility Assay

Current biocompatibility analysis methods are slow and requirehistological analysis. Described herein is a high throughput in vivobiocompatibility assay, useful for assessing the relativebiocompatibility of alginate polymers.

In the high throughput in vivo biocompatibility assay described herein,modified alginate polymers and an unmodified alginate control areinjected in an array format on the back of an animal test subject tofacilitate high-throughput screening. In preferred embodiments, theanimal test subject is a mouse. After injection, cathepsin activity atthe point of injection of the modified alginates was compared tocathepsin activity at the point of injection the unmodified alginate tocompare the foreign body response to the implanted alginates using invivo fluorescence imaging. In preferred embodiments, thebiocompatibility of the materials was assessed at 14 days post injectionusing in vivo fluorescence imaging.

In preferred embodiments, the high throughput in vivo biocompatibilityassay described herein is used to identify modified alginates whichinduce a lower foreign body response than unmodified alginate. Thefluorescence intensity measured at the implantation site of modifiedalginates was compared with the fluorescence intensity measured at theimplantation site of an unmodified alginate. In preferred embodiments,modified alginates exhibiting smaller fluorescence intensity at theimplantation site than the fluorescence intensity measured at theimplantation site of unmodified alginates were qualitativelycharacterized as biocompatible. Conversely, modified alginatesexhibiting greater fluorescence intensity at the implantation site thanthe fluorescence intensity measured at the implantation site ofunmodified alginates were characterized as not biocompatible.

The high throughput in vivo biocompatibility assay described above canalso be used to characterize the ability of modified alginates to formmechanically stable hydrogels in vivo. In preferred embodiments, the invivo stability of the alginate gels was assessed at 28 days postinjection.

In preferred embodiments, modified alginates gels which remained at thesite of injection after 28 days were characterized as capable of formingmechanically stable hydrogels in vivo. Conversely, modified alginategels which were not present at the site of injection after 28 days weredeemed to not capable of forming mechanically stable hydrogels in vivo.

C. In Vivo Screening of Modified Alginates to Quantify Biocompatibility

Further described herein is an in vivo method for quantifying thebiocompatibility of modified alginates.

In this method, a modified alginate polymers is injected on the back ofan animal test subject. In preferred embodiments, the animal testsubject is a mouse. After injection, cathepsin activity at the point ofinjection of the modified alginates was measured using in vivofluorescence assay. In preferred embodiments, the fluorescence assay wasconducted at 7 days post injection using in vivo fluorescence imaging.In preferred embodiments, the fluorescence intensity was measured andnormalized to the fluorescence response measured using unmodifiedalginate in order to quantify the biocompatibility of the modifiedalginates.

In preferred embodiments, the modified alginate polymer induces a lowerforeign body response than unmodified alginate (i.e. the fluorescenceresponse normalized to unmodified alginate is less that 100%). In someembodiments, the modified alginate polymer is biocompatible such thatthe fluorescence response normalized to unmodified alginate measuredusing the in vivo biocompatibility assay described herein is less than95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40%. Inpreferred embodiments, the modified alginate polymer is biocompatiblesuch that the fluorescence response normalized to unmodified alginatemeasured using the in vivo biocompatibility assay described herein isless than 75%, more preferably less than 65%, and most preferably lessthan 50%.

V. Methods of Use

Alginates are used in a variety of applications in the food,pharmaceutical, cosmetic, agriculture, printing, and textile industries.Alginates are widely employed in the food industry as thickening,gelling, stabilizing, bodying, suspending, and emulsifying agents.Alginates can be used as a matrix to control the delivery oftherapeutic, prophylactic, and/or diagnostic agents. Alginates can beincorporated in pharmaceutical compositions as excipients, where theycan act as viscosifiers, suspension agents, emulsifiers, binders, anddisintigrants. Alginate also used as a dental impression material,component of wound dressings, and as a printing agent. One of ordinaryskill in the art will recognize that the modified alginates disclosedherein can be used in any application for which alginates are currentlyemployed.

It is specifically contemplated that modified alginates described hereincan be used in applications where improved biocompatibility and physicalproperties (such as being anti-fibrotic), as compared to commerciallyavailable alginates, are preferred.

The modified alginates and coated products described herein can be usedto treat abroad spectrum of diseases, disorders, and conditions. Forexample, capsules that include cells or tissues can be used to treatdisorders characterized by a need for a product produced by the cell ortissue or of a reaction mediated by a product of the cell. For example,the cell or cell product can metabolize glucocerebroside or detoxifycompounds. For type I and III Gaucher's disease, enzyme replacementtreatment with intravenous recombinant glucocerebrosidase is generallyused to hydrolyze the beta-glucosidic linkage of, an intermediate inglyclipid metabolism. Toxin-specific antibodies can be used inprophylaxis or treatment of infections caused by bacteria such asBacillus anthracis and Clostridium difficile. In some embodiments, thecell or tissue can produce a product useful to treat a disorder. Forexample, where the cell is an islet cell and the disorder is diabetes.In some embodiments, the product can include a cell that metabolizes ormodifies a substrate produced by the subject.

TABLE 2 List of disorders and the cells or cell-produced substance thatcan be used to treat the disorder. Cell or Cell-produced SubstanceDisorder Stem cells Neurodegenerative diseases, diabetes, heart diseasesand many other conditions Pancreatic islet cells Diabetes Autologoushaemopoietic stem cell transplantation Chronic inflammatory autoimmunediseases including severe forms of scleroderma, multiple sclerosis, andlupus Chimeric antigen receptor T cells Cancers to be treated includenon-solid cancers and solid cacers, for examples, carcinoma, blastoma,and sarcoma, and leukemia or lymphoid malignancies, benign and malignanttumors, and malignancies e.g., sarcomas, carcinomas, and melanomas.Hepatocyte cell therapy Liver diseases such as cirrhosis, liver cancerand hepatitis. Allogeneic differentiated osteoblastic Orthopedicconditions including cells impaired fracture, a delayed union fracture,osteonecrosis and osteoporosis. Chemically induced neuron cells fromneurodegenerative disorder selected pluripotent cells from the groupconsisting of Alzheimer's Disease (AD), Huntington's Disease (HD),Parkinson's Disease (PD) Amyotrophic Lateral Sclerosis (ALS), MultipleSclerosis (MS) and Cerebral Palsy (CP), Dentatorubro-pallidoluysianAtrophy (DRPLA), Neuronal Intranuclear Hyaline Inclusion Disease(NIHID), dementia with Lewy bodies, Down's Syndrome, Hallervorden-Spatzdisease, prion diseases, argyrophilic grain dementia, cortocobasaldegeneration, dementia pugilistica, diffuse neurofibrillary tangles,Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease,Jakob-Creutzfeldt disease, Niemann- Pick disease type 3, progressivesupranuclear palsy, subacute sclerosing panencephalitis, SpinocerebellarAtaxias, Pick's disease, and dentatorubral- pallidoluysian atrophyDisorders of Amino Acid Metabolism phenylalanine hydroxylasePhenylketonuria (PKU) biopterin cofactor Malignant PKUfumarylacetoacetate hydrolase Type 1 tyrosinemia tyrosineaminotransferase Type 2 tyrosinemia protein(s) involved in tyrosineAlkaptonuria breakdown cystathionine-β-synthase or Homocystinuria andmethylenetetrahydrofolate reductase or Hyperhomocysteinemia protein(s)involved in formation of the methylcobalamin form of vitamin B₁₂branched-chain ketoacid Maple Syrup Urine disease dehydrogenase complexDisorders of Organic Acid Metabolism propionyl-CoA carboxylase PropionicAcidemia pyruvate carboxylase and 3- Multiple Carboxylase deficiencymethylcrotonyl-CoA carboxylase methylmalonyl-CoA mutase; MethylmalonicAcidemia protein(s) involved in vitamin B₁₂ metabolism Disorders ofFatty Acid Metabolism protein(s) involved in regulation orHyperlipidemia and utilization of lipoproteins hypercholesterolemia verylong chain acyl-CoA Fatty Acid Oxidation disorders dehydrogenase; longchain hydroxyacyl-CoA dehydrogenase; dehydrogenase; medium chain acyl-CoA dehydrogenase; short chain acyl CoA dehydrogenase; short chainhydroxyacyl-CoA dehydrogenase protein(s) involved in glycogenolysisGlycogen Storage diseases galactose-1-phosphate uridyl Galactosemiatransferase enzyme(s) that build the carbohydrate Congenital Disordersof Glycosylation side-chains on proteins Disorders of Purine andPyrimidine Metabolism protein(s) involved in balance between PurineOverproduction purine synthesis and disposal hypoxanthinephosphoribosyl- Lesch-Nyhan syndrome transferase Lysosomal StorageDisorders cerebrosidase Gaucher disease Types I and IIbeta-hexosaminidase A Tay-Sachs disease α-galactosidase Fabry diseaseα-iduronidase (Hurler Hurler syndrome, Hunter syndrome syndrome);iduronate sultatase (Hunter syndrome); iduronate sultatase (Huntersyndrome) enzyme(s) involved in heparan sulfate Sanfilippo syndromedegradation arylsulfatase B Maroteaux-Lamy syndrome galactose6-sulfatase; β-galactosidase Morquio syndrome carbamyl phosphatesynthetase; Disorders of Urea Formation ornithine transcarbamylase;citrullinemia; argininosuccinic aciduria Disorders of PeroxisomalMetabolism protein(s) involved in branched-chain Refsum disease fattyacid production and/or breakdown alanine-glyoxylate transaminaseAlanine-glyoxylate transaminase defect Cellular metabolic enzymes Enzymedeficiency diseases Muscle cell metabolic enzymes metabolic disorders ofthe muscle (e.g. Pompe's disease)

A. Encapsulation of Cells

Alginate can be ionically cross-linked with divalent cations, in water,at room temperature, to form a hydrogel matrix. See, for example, inU.S. Pat. No. 4,352,883 to Lim. In the Lim process, an aqueous solutioncontaining the biological materials to be encapsulated is suspended in asolution of a water soluble polymer, the suspension is formed intodroplets which are configured into discrete capsules by contact withmultivalent cations, then the surface of the capsules is crosslinkedwith poly amino acids to form a semipermeable membrane around theencapsulated materials.

The water soluble polymer with charged side groups is crosslinked byreacting the polymer with an aqueous solution containing multivalentions of the opposite charge, either multivalent cations if the polymerhas acidic side groups or multivalent anions if the polymer has basicside groups. The preferred cations for cross-linking of the polymerswith acidic side groups to form a hydrogel are divalent and trivalentcations such as copper, calcium, aluminum, magnesium, strontium, barium,and tin, although di-, tri- or tetra-functional organic cations such asalkylammonium salts, e.g., R₃N+—\∧∧/—+NR₃ can also be used. Aqueoussolutions of the salts of these cations are added to the polymers toform soft, highly swollen hydrogels and membranes. The higher theconcentration of cation or the higher the valence, the greater thedegree of cross-linking of the polymer. Concentrations from as low as0.005 M have been demonstrated to cross-link the polymer. Higherconcentrations are limited by the solubility of the salt.

The preferred anions for cross-linking of polymers containing basicsidechains to form a hydrogel are divalent and trivalent anions such aslow molecular weight dicarboxylic acids, for example, terepthalic acid,sulfate ions and carbonate ions. Aqueous solutions of the salts of theseanions are added to the polymers to form soft, highly swollen hydrogelsand membranes, as described with respect to cations.

A variety of poly cations can be used to complex and thereby stabilizethe polymer hydrogel into a semi-permeable surface membrane. Examples ofmaterials that can be used include polymers having basic reactive groupssuch as amine or imine groups, having a preferred molecular weightbetween 3,000 and 100,000, such as polyethylenimine and polylysine.These are commercially available. One poly cation is poly(L-lysine);examples of synthetic polyamines are: polyethyleneimine,poly(vinylamine), and poly(allyl amine). There are also natural polycations such as the polysaccharide, chitosan.

Polyanions that can be used to form a semi-permeable membrane byreaction with basic surface groups on the polymer hydrogel includepolymers and copolymers of acrylic acid, methacrylic acid, and otherderivatives of acrylic acid, polymers with pendant SO₃H groups such assulfonated polystyrene, and polystyrene with carboxylic acid groups.

In a preferred method, cells are encapsulated in a modified alginatepolymer. In a preferred embodiment, modified alginate capsules arefabricated from solution of modified alginate containing suspended cellsusing the encapsulator (such as an Inotech encapsulator). In someembodiments, modified alginates are ionically crosslinked with apolyvalent cation, such as Ca²⁺, Ba²⁺, or Sr²⁺. In particularlypreferred embodiments, the modified alginate is crosslinked using BaCl₂.In some embodiments, the capsules are further purified after formation.In preferred embodiments, the capsules are washed with, for example,HEPES solution, Krebs solution, and/or RPMI-1640 medium.

Cells can be obtained directed from a donor, from cell culture of cellsfrom a donor, or from established cell culture lines. In the preferredembodiments, cells are obtained directly from a donor, washed andimplanted directly in combination with the polymeric material. The cellsare cultured using techniques known to those skilled in the art oftissue culture. In the preferred embodiment, the cells areautologous—i.e., derived from the individual into which the cells are tobe transplanted, but may be allogeneic or heterologous.

Cell attachment and viability can be assessed using scanning electronmicroscopy, histology, and quantitative assessment with radioisotopes.The function of the implanted cells can be determined using acombination of the above-techniques and functional assays. For example,in the case of hepatocytes, in vivo liver function studies can beperformed by placing a cannula into the recipient's common bile duct.Bile can then be collected in increments. Bile pigments can be analyzedby high pressure liquid chromatography looking for underivatizedtetrapyrroles or by thin layer chromatography after being converted toazodipyrroles by reaction with diazotized azodipyrrolesethylanthranilate either with or without treatment with P-glucuronidase.Diconjugated and monoconjugated bilirubin can also be determined by thinlayer chromatography after alkalinemethanolysis of conjugated bilepigments. In general, as the number of functioning transplantedhepatocytes increases, the levels of conjugated bilirubin will increase.Simple liver function tests can also be done on blood samples, such asalbumin production. Analogous organ function studies can be conductedusing techniques known to those skilled in the art, as required todetermine the extent of cell function after implantation. For example,islet cells of the pancreas may be delivered in a similar fashion tothat specifically used to implant hepatocytes, to achieve glucoseregulation by appropriate secretion of insulin to cure diabetes. Otherendocrine tissues can also be implanted. Studies using labeled glucoseas well as studies using protein assays can be performed to quantitatecell mass on the polymer scaffolds. These studies of cell mass can thenbe correlated with cell functional studies to determine what theappropriate cell mass is. In the case of chondrocytes, function isdefined as providing appropriate structural support for the surroundingattached tissues.

This technique can be used to provide multiple cell types, includinggenetically altered cells, within a three-dimensional scaffolding forthe efficient transfer of large number of cells and the promotion oftransplant engraftment for the purpose of creating a new tissue ortissue equivalent. It can also be used for immunoprotection of celltransplants while a new tissue or tissue equivalent is growing byexcluding the host immune system.

Examples of cells which can be implanted as described herein includechondrocytes and other cells that form cartilage, osteoblasts and othercells that form bone, muscle cells, fibroblasts, and organ cells. Asused herein, “organ cells” includes hepatocytes, islet cells, cells ofintestinal origin, cells derived from the kidney, and other cells actingprimarily to synthesize and secret, or to metabolize materials. Apreferred cell type is a pancreatic islet cell.

The polymeric matrix can be combined with humoral factors to promotecell transplantation and engraftment. For example, the polymeric matrixcan be combined with angiogenic factors, antibiotics,antiinflammatories, growth factors, compounds which inducedifferentiation, and other factors which are known to those skilled inthe art of cell culture.

For example, humoral factors could be mixed in a slow-release form withthe cell-alginate suspension prior to formation of implant fortransplantation. Alternatively, the hydrogel could be modified to bindhumoral factors or signal recognition sequences prior to combinationwith isolated cell suspension.

The techniques described herein can be used for delivery of manydifferent cell types to achieve different tissue structures. In thepreferred embodiment, the cells are mixed with the hydrogel solution andinjected directly into a site where it is desired to implant the cells,prior to hardening of the hydrogel. However, the matrix may also bemolded and implanted in one or more different areas of the body to suita particular application. This application is particularly relevantwhere a specific structural design is desired or where the area intowhich the cells are to be implanted lacks specific structure or supportto facilitate growth and proliferation of the cells.

The site, or sites, where cells are to be implanted is determined basedon individual need, as is the requisite number of cells. For cellshaving organ function, for example, hepatocytes or islet cells, themixture can be injected into the mesentery, subcutaneous tissue,retroperitoneum, properitoneal space, and intramuscular space. Forformation of cartilage, the cells are injected into the site wherecartilage formation is desired. One could also apply an external mold toshape the injected solution. Additionally, by controlling the rate ofpolymerization, it is possible to mold the cell-hydrogel injectedimplant like one would mold clay. Alternatively, the mixture can beinjected into a mold, the hydrogel allowed to harden, then the materialimplanted.

B. Coating Products and Surfaces

Medical products can be coated with the disclosed modified alginatepolymers using a variety of techniques, examples of which includespraying, dipping, and brush coating. Polymer coatings are typicallyapplied to the surface to be coated by dissolving a polymer in anappropriate, preferably organic solvent, and applying by spraying,brushing, dipping, painting, or other similar technique. The coatingsare deposited on the surface and associate with the surfaces vianon-covalent interactions. The coated products and surfaces that resultare specifically contemplated and disclosed.

In some embodiments, the surface may be pretreated with an appropriatesolution or suspension to modify the properties of the surface, andthereby strengthen the non-covalent interactions between the modifiedsurface and the coating.

The polymer solution is applied to a surface at an appropriatetemperature and for a sufficient period of time to form a coating on thesurface, wherein the coating is effective in forming an anti-fibroticsurface. Typical temperatures include room temperature, although highertemperatures may be used. Typical time periods include 5 minutes orless, 30 minutes or less, 60 minutes or less, and 120 minutes or less.In some embodiments the solution can be applied for 120 minutes orlonger to form a coating with the desired anti-fibrotic activity.However, preferably shorter time periods are used. Anti-fibroticactivity can be measured in any of the ways disclosed herein or known inthe art. Preferably the anti-fibrotic activity can be the foreign bodyresponse determined as described herein.

The disclosed modified alginate polymers can be covalently ornon-covalently associated with the products, devices, and surfaces. Forthose embodiments where the modified alginate polymer is covalentlyassociated with the product, device, or surface, the polymer can beattached to the product, device, or surface by, for example,functionalizing the product, device, or surface with a reactionfunctional group, such as a nucleophilic group, and reacting thenucleophilic group with a reaction functional group on the polymer, suchas an electrophilic group. Alternatively, the polymer can befunctionalized with a nucleophilic group which is reacted with anelectrophilic group on the product, device, or surface.

In particular embodiments, the modified alginate polymer isnon-covalently associated with the product, device, or surface. Thepolymer can be applied to the product, device, or surface by spraying,wetting, immersing, dipping, painting, bonding or adhering or otherwiseproviding a product, device, or surface with a compound with themodified alginate polymer. In one embodiment, the polymer is applied byspraying, painting, or dipping or immersing. For example, a polymerpaint can be prepared by dissolving the modified alginate polymer in asuitable solvent (generally aqueous), and optionally sonicating thesolution to ensure the polymer is completely dissolved. The product,device, or surface to be coated can be immersed in the polymer solutionfor a suitable period of time, e.g., 5 seconds, followed by drying, suchas air drying. The procedure can be repeated as many times as necessaryto achieve adequate coverage. The thickness of the coating is generallyfrom about 1 nm to about 1 cm, preferably from about 10 nm to 1 mm, morepreferably from about 100 nm to about 100 microns.

The coating can be applied at the time the product, device, or surfaceis manufactured or can be applied subsequent to manufacture of theproduct, device, or surface. In some embodiments, the coating is appliedto the product, device, or surface immediately prior to use of theproduct, device, or surface. This is referred to an intraoperativecoating. “Immediately prior,” as used herein, mean within 1, 2, 5, 10,15, 20, 30, 45, 60, 75, 90, 120, 150, 180 minutes or greater ofimplantation or use. In some embodiments, the product, device, orsurface is coated at the hospital, e.g., in the operating room, with 20,15, 10, or 5 minutes of implantation or use. Coating immediately priorto use may overcome limitations of products, devices, and surfacescoated at the time of manufacture, such as damage of the coating duringstorage and/or transportation of the product, device, or surface and/ordecrease in the efficacy of the coating over time as the coating isexposed to environmental conditions, which may be harsh (e.g., hightemps, humidity, exposure to UV light, etc.).

The coated medical products can be used for the known uses and purposesof uncoated or differently coated forms of the medical products.

I. Medical Products

Medical products useful for coating include any types of medical devicesused, at least in part, for implantation in the body of a patient.Examples include, but are not limited to, implants, implantable medicalproducts, implantable devices, catheters and other tubes (includingurological and biliary tubes, endotracheal tubes, wound drain tubes,needle injection catheters, peripherably insertable central venouscatheters, dialysis catheters, long-term tunneled central venouscatheters peripheral venous catheters, short term central venouscatheters, arterial catheters, pulmonary catheters, Swan-Ganz catheters,urinary catheters, peritoneal catheters), vascular catheter ports, bloodclot filters, urinary devices (including long-term urinary devices,tissue bonding urinary devices, artificial urinary sphincters, urinarydilators), shunts (including ventricular or arterio-venous shunts, stenttransplants, biliary stents, intestinal stents, bronchial stents,esophageal stents, ureteral stents, and hydrocephalus shunts), balloons,pacemakers, implantable defibrillators, orthopedic products (includingpins, plates, screws, and implants), transplants (including organs,vascular transplants, vessels, aortas, heart valves, and organreplacement parts), prostheses (including breast implants, penileprostheses, vascular grafting prostheses, heart valves, artificialjoints, artificial larynxes, otological implants, artificial hearts,artificial blood vessels, and artificial kidneys), aneurysm-fillingcoils and other coil devices, transmyocardial revascularization devices,percutaneous myocardial revascularization devices, tubes, fibers, hollowfibers, membranes, blood containers, titer plates, adsorber media,dialyzers, connecting pieces, sensors, valves, endoscopes, filters, pumpchambers, scalpels, needles, scissors (and other devices used ininvasive surgical, therapeutic, or diagnostic procedures), and othermedical products and devices intended to have anti-fibrotic properties.The expression “medical products” is broad and refers in particular toproducts that come in contact with blood briefly (e.g., endoscopes) orpermanently (e.g., stents).

Useful medical products are balloon catheters and endovascularprostheses, in particular stents. Stents of a conventional design have afiligree support structure composed of metallic struts. The supportstructure is initially provided in an unexpanded state for insertioninto the body, and is then widened into an expanded state at theapplication site. The stent can be coated before or after it is crimpedonto a balloon. A wide variety of medical endoprostheses or medicalproducts or implants for highly diverse applications and are known. Theyare used, for example, to support vessels, hollow organs, and ductalsystems (endovascular implants), to attach and temporarily affix tissueimplants and tissue transplants, and for orthopedic purposes such aspins, plates, or screws.

The modified alginate polymers can be applied to, absorbed into, orcoupled to, a variety of different substrates and surfaces. Examples ofsuitable materials include metals, metallic materials, ceramics,polymers, fibers, inert materials such as silicon, and combinationsthereof.

Suitable polymeric materials include, but are not limited to, styreneand substituted styrenes, ethylene, propylene, poly(urethane)s,acrylates and methacrylates, acrylamides and methacrylamides,polyesters, polysiloxanes, polyethers, poly(orthoester),poly(carbonates), poly(hydroxyalkanoate)s, copolymers thereof, andcombinations thereof.

Substrates can be in the form of, or form part of, films, particles(nanoparticles, microparticles, or millimeter diameter beads), fibers(wound dressings, bandages, gauze, tape, pads, sponges, including wovenand non-woven sponges and those designed specifically for dental orophthalmic surgeries), sensors, pacemaker leads, catheters, stents,contact lenses, bone implants (hip replacements, pins, rivets, plates,bone cement, etc.), or tissue regeneration or cell culture devices, orother medical devices used within or in contact with the body.

Implants coated with modified alginate polymer coatings are describedherein. “Implants” are any object intended for placement in the body ofa mammal, such as a human, that is not a living tissue. Implants are aform of medical product. Implants include naturally derived objects thathave been processed so that their living tissues have been devitalized.As an example, bone grafts can be processed so that their living cellsare removed, but so that their shape is retained to serve as a templatefor ingrowth of bone from a host. As another example, naturallyoccurring coral can be processed to yield hydroxyapatite preparationsthat can be applied to the body for certain orthopedic and dentaltherapies. An implant can also be an article comprising artificialcomponents. The term “implant” can be applied to the entire spectrum ofmedical devices intended for placement in a human body or that of amammal, including orthopedic applications, dental applications, ear,nose, and throat (“ENT”) applications, and cardiovascular applications.

In some embodiments, “implant” as used herein refers to a macroscopiccomposition including a device for implantation or a surface of a devicefor implantation and a modified alginate polymer coating. In theseembodiments, the term “implant” does not encompass nanoparticles and/ormicroparticles. “Macroscopic” as used herein generally refers todevices, implants, or compositions that can be viewed by the unaidedeye.

Examples of implantable medical devices and medical devices andmechanical structures that can use a bio-compatible coating include, butare not limited to, stents, conduits, scaffolds, cardiac valve rings,cardiovascular valves, pacemakers, hip replacement devices, implantedsensor devices, esophageal stents, heart implants, bio-compatiblelinings for heart valves, dialysis equipment and oxygenator tubing forheart-lung by-pass systems.

In general, a stent is a device, typically tubular in shape, that isinserted into a lumen of the body, such as a blood vessel or duct, toprevent or counteract a localized flow constriction. The purpose of astent, in some cases, is to mechanically prop open a bodily fluidconduit. Stents are often used to alleviate diminished blood flow toorgans and extremities in order to maintain adequate delivery ofoxygenated blood. The most common use of stents is in coronary arteries,but they are also widely used in other bodily conduits, such as, forexample, central and peripheral arteries and veins, bile ducts, theesophagus, colon, trachea, large bronchi, ureters, and urethra.Frequently, stents inserted into a lumen are capable of being expandedafter insertion or are self-expanding. For example, metal stents aredeployed into an occluded artery using a balloon catheter and expandedto restore blood flow. For example, stainless steel wire mesh stents arecommercially available from Boston Scientific, Natick, Mass.

In some embodiments, the implant is an orthopedic implant. An“orthopedic implant” is defined as an implant which replaces bone orprovides fixation to bone, replaces articulating surfaces of a joint,provides abutment for a prosthetic, or combinations thereof or assistsin replacing bone or providing fixation to bone, replacing articulatingsurfaces of a joint, providing abutment for a prosthetic, andcombinations thereof.

Orthopedic implants can be used to replace bone or provide fixation tobone, replace articulating surfaces of a joint, provide abutment for aprosthetic, or combinations thereof or assist in replacing bone orproviding fixation to bone, replacing articulating surfaces of a joint,providing abutment for a prosthetic, including dental applications, andcombinations thereof.

Suitable orthopedic implants include, but are not limited to, wire,Kirschner wire, bone plates, screws, pins, tacs, rods, nails, nuts,bolts, washers, spikes, buttons, wires, fracture plates, reconstructionand stabilizer devices, endo- and exoprostheses (articulating andnon-articulating), intraosseous transcutaneous prostheses, spacers,mesh, implant abutments, anchors, barbs, clamps, suture, interbodyfusion devices, tubes of any geometry, scaffolds, and combinationsthereof.

In other embodiments, the implant is an ear, nose, and/or throat (“ENT”)implant. Exemplary ENT implants include, but are not limited to, eartubes, endotracheal tubes, ventilation tubes, cochlear implants and boneanchored hearing devices.

In other embodiments, the implant is a cardiovascular implant. Exemplarycardiovascular implants are cardiac valves or alloplastic vessel wallsupports, total artificial heart implants, ventricular assist devices,vascular grafts, stents, electrical signal carrying devices such aspacemaker and neurological leads, defibrillator leads, and the like.

Implants can be prepared from a variety of materials. In someembodiments, the material is biocompatible. In some embodiments, thematerial is biocompatible and non-biodegradable. Exemplary materialsinclude metallic materials, metal oxides, polymeric materials, includingdegradable and non-degradable polymeric materials, ceramics, porcelains,glass, allogeneic, xenogenic bone or bone matrix; genetically engineeredbone; and combinations thereof.

Suitable metallic materials include, but are not limited to, metals andalloys based on titanium (such as nitinol, nickel titanium alloys,thermo-memory alloy materials), stainless steel, tantalum, palladium,zirconium, niobium, molybdenum, nickel-chrome, or certain cobalt alloysincluding cobalt-chromium and cobalt-chromium-nickel alloys such asELGILOY® and PHYNOX®. Useful examples include stainless steel grade 316(SS 316L) (comprised of Fe, <0.3% C, 16-18.5% Cr, 10-14% Ni, 2-3% Mo,<2% Mn, <1% Si, <0.45% P, and <0.03% S), tantalum, chromium molybdenumalloys, nickel-titanium alloys (such as nitinol) and cobalt chromiumalloys (such as MP35N, ASTM Material Designation: 35Co-35Ni-20Cr-10Mo).Typical metals currently in use for stents include SS 316L steel andMP35N. See also, “Comparing and Optimizing Co—Cr Tubing for StentApplications,” Poncin, P, Millet, C., Chevy, J, and Profit, J. L.,Materials & Processes for Medical Devices Conference, August 2004, ASMInternational.

Suitable ceramic materials include, but are not limited to, oxides,carbides, or nitrides of the transition elements such as titaniumoxides, hafnium oxides, iridium oxides, chromium oxides, aluminumoxides, and zirconium oxides. Silicon based materials, such as silica,may also be used.

Suitable polymeric materials include, but are not limited to,polystyrene and substituted polystyrenes, polyethylene, polypropylene,polyacetylene, polystyrene, TEFLON®, poly(vinyl chloride) (PVC),polyolefin copolymers, poly(urethane)s, polyacrylates andpolymethacrylates, polyacrylamides and polymethacrylamides, polyesters,polysiloxanes, polyethers, poly(orthoester), poly(carbonates),poly(hydroxyalkanoate)s, polyfluorocarbons, PEEK®, Teflon®(polytetrafluoroethylene, PTFE), silicones, epoxy resins, Kevlar®,Dacron® (a condensation polymer obtained from ethylene glycol andterephthalic acid), nylon, polyalkenes, phenolic resins, natural andsynthetic elastomers, adhesives and sealants, polyolefins, polysulfones,polyacrylonitrile, biopolymers such as polysaccharides and naturallatex, collagen, cellulosic polymers (e.g., alkyl celluloses, etc.),polysaccharides, poly(glycolic acid), poly(L-lactic acid) (PLLA), apolydioxanone (PDA), or racemic poly (lactic acid), polycarbonates,(e.g., polyamides (nylon); fluoroplastics, carbon fiber, and blends orcopolymers thereof.

The polymer can be covalently or non-covalently associated with thesurface; however, in particular embodiments, the polymer isnon-covalently associated with the surface. The polymer can be appliedby a variety of techniques in the art including, but not limited to,spraying, wetting, immersing, dipping, such as dip coating (e.g.,intraoperative dip coating), painting, or otherwise applying ahydrophobic, poly cationic polymer to a surface of the implant.

A surface of a product adapted for use in a medical environment can becapable of sterilization using autoclaving, biocide exposure,irradiation, or gassing techniques, like ethylene oxide exposure.Surfaces found in medical environments include the inner and outeraspects of various instruments and devices, whether disposable orintended for repeated uses. 2. Hydrogels Medical products can also bemade of or using hydrogels. The disclosed modified alginate polymers canform hydrogels for this and other purposes. Products made of otherhydrogels can also be coated with the disclosed modified alginatepolymers. Thus, the disclosed modified alginate polymers can be used asa coating on a product or surface or can be used as the product itself.Hydrogels are three-dimensional, hydrophilic, polymeric networks capableof imbibing large amounts of water or biological fluids (Peppas et al.Eur. J. Pharm. Biopharm. 2000, 50, 27-46). These networks are composedof homopolymers or copolymers, and are insoluble due to the presence ofchemical crosslinks or physical crosslinks, such as entanglements orcrystallites. Hydrogels can be classified as neutral or ionic, based inthe nature of the side groups. In addition, they can be amorphous,semicrystalline, hydrogen-bonded structures, supermolecular structuresand hydrocolloidal aggregates (Peppas, N. A. Hydrogels. In: Biomaterialsscience: an introduction to materials in medicine; Ratner, B. D.,Hoffman, A. S., Schoen, F. J., Lemons, J. E., Eds; Academic Press, 1996,pp. 60-64; Peppas et al., Eur. J. Pharm. Biopharm. 2000, 50, 27-46).Hydrogels can be prepared from synthetic or natural monomers orpolymers. Preferred hydrogels herein are the disclosed modified alginatepolymers.

Hydrogels can be prepared from synthetic polymers such as poly(acrylicacid) and its derivatives [e.g. poly (hydroxy ethyl methacrylate)(pHEMA)], poly(N-isopropylacrylamide), poly (ethylene glycol) (PEG) andits copolymers and poly (vinyl alcohol) (PVA), among others (Bell andPeppas, Adv. Polym. Sci. 722:125-175 (1995); Peppas et al., Eur. J.Pharm. Biopharm. 50:27-46 (200); Lee and Mooney, Chem. Rev.707:1869-1879 (2001)). Hydrogels prepared from synthetic polymers are ingeneral non-degradable in physiologic conditions. Hydrogels can also beprepared from natural polymers including, but not limited to,polysaccharides, proteins, and peptides. The disclosed modified alginatepolymers are a preferred example. These networks are in general degradedin physiological conditions by chemical or enzymatic means.

In some embodiments, the hydrogel is non-degradable under relevant invitro and in vivo conditions. Stable hydrogel coatings are necessary forcertain applications including central venous catheters coating, heartvalves, pacemakers and stents coatings. In other cases, hydrogeldegradation may be a preferential approach such as in tissue engineeringconstructs.

In some embodiments, the hydrogel can be formed by dextran. Dextran is abacterial polysaccharide, consisting essentially of α-1,6 linkedD-glucopyranose residues with a few percent of α-1,2, α-1,3, orα-1,4-linked side chains. Dextran is widely used for biomedicalapplications due to its biocompatibility, low toxicity, relatively lowcost, and simple modification. This polysaccharide has been usedclinically for more than five decades as a plasma volume expander,peripheral flow promoter and antithrombolytic agent (Mehvar, R. J.Control. Release 2000, 69, 1-25). Furthermore, it has been used asmacromolecular carrier for delivery of drugs and proteins, primarily toincrease the longevity of therapeutic agents in the circulation. Dextrancan be modified with vinyl groups either by using chemical or enzymaticmeans to prepare gels (Ferreira et al. Biomaterials 2002, 23,3957-3967).

Dextran-based hydrogels prevent the adhesion of vascular endothelial,smooth muscle cells, and fibroblasts (Massia, S. P.; Stark, J. J.Biomed. Mater. Res. 2001, 56, 390-399. Ferreira et al. 2004, J. Biomed.Mater. Res. 68A, 584-596) and dextran surfaces prevent proteinadsorption (Osterberg et al. J. Biomed. Mat. Res. 1995, 29, 741-747).

As described herein, the disclosed modified alginate polymers can beused to encapsulate cells. In some embodiments, the encapsulated cellscan be fabricated into a macrodevice. For example, in some embodiments,cells encapsulated in modified alginate hydrogel can be coated onto asurface, such as a planar surface. In some embodiments, capsulescontaining cells can be adhered to tissue of a subject using abiocompatible adhesive. In other embodiments, capsules containing cellscan be coated onto a medical device suitable for implantation.

C. Treatment of Diseases or Disorders

Encapsulated cells can be transplanted into a patient in need thereof totreat a disease or disorder. In some embodiments, the encapsulated cellsare obtained from a genetically non-identical member of the samespecies. In alternative embodiments, the encapsulated cells are obtainedfrom a different species than the patient. In preferred embodiments,hormone- or protein-secreting cells are encapsulated and transplantedinto a patient to treat a disease or disorder.

In preferred embodiments, the disease or disorder is caused by orinvolves the malfunction hormone- or protein-secreting cells in apatient. In a preferred embodiment, the disease or disorder is diabetes.

Medical products, devices, and surfaces coated with a modified alginatepolymer can be transplanted or implanted into a patient in need thereofto treat a disease or disorder.

The disclosed capsules, products, devices, and surfaces can remainsubstantially free of fibrotic effects, or can continue to exhibit areduced foreign body response, for 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 2 months, 3 months, 4months, 5 months, 6 months, 7 months, 8, months, 9 months, 10 months, 11months, 1 year, 2 years, or longer after administration or implantation.

The disclosed capsules, products, devices, and surfaces can beadministered or implanted alone or in combination with any suitable drugor other therapy. Such drugs and therapies can also be separatelyadministered (i.e., used in parallel) during the time the capsules,products, devices, and surfaces are present in a patient. Although thedisclosed capsules, products, devices, and surfaces reduce fibrosis andimmune reaction to the capsules, products, devices, and surfaces, use ofanti-inflammatory and immune system suppressing drugs together with orin parallel with the capsules, products, devices, and surfaces is notexcluded. In preferred embodiments, however, the disclosed capsules,products, devices, and surfaces are used without the use ofanti-inflammatory and immune system suppressing drugs. In preferredembodiments, fibrosis remains reduced after the use, concentration,effect, or a combination thereof, of any anti-inflammatory or immunesystem suppressing drug that is used falls below an effective level. Forexample, fibrosis can remain reduced for 2 weeks, 3 weeks, 4 weeks, 5weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 2 months, 3 months,4 months, 5 months, 6 months, 7 months, 8, months, 9 months, 10 months,11 months, 1 year, 2 years, or longer after the use, concentration,effect, or a combination thereof, of any anti-inflammatory or immunesystem suppressing drug that is used falls below an effective level.

The present invention will be further understood by reference to thefollowing non-limiting examples.

EXAMPLES Example 1: Combinatorial Synthesis of Chemically ModifiedAlginates

The determinate parameters governing material biocompatibility arepoorly understood. Accordingly, the rational design and synthesis ofmodified alginates possessing improved biocompatibility is challenging.In an effort to identify modified alginates with improvedbiocompatibility and physical properties, a combinatorial approach wasused to prepare a library of modified alginates possessing a range ofcovalent modifications.

I. General Combinatorial Strategy

A pool of twelve alcohols, nine amines, two amines used to introduce anazide moiety (one amine containing an azide moiety and one aminecontaining an iodide moiety to be converted to an azide moietysubsequent to amidation), and nineteen alkynes with a range of differentchemical structures, hydrophobicities/hydrophilicities, hydrogen-bondingpotentials, and charge states were selected as reagents for thecombinatorial synthesis of modified alginates. With the knowledge thatimpurities present in alginate polymers have been shown to limit thebiocompatibility of implanted alginates, ultra-pure, low viscosityalginate (UPLVG, FMC Biopolymers) was selected as a starting materialfor modification experiments.

Alkynes Used as Reagents for 1,3-Dipolar Cycloaddition

Alcohols Used as Reagents for Esterification

Amines Used as Reagents for Amidation

Amines Used as Reagents to Introduce Azide Moieties

Unmodified alginate polymer was covalently modified by reaction withone, two, or three the esters, amines, and/or alkynes shown above in acombinatorial fashion. FIG. 1 shows the general structure of themodified alginates obtained using this method.

2. Representative Reaction Conditions

Due to the parallel and combinatorial nature of the modificationprocess, synthetic reactions were performed using a robotic core module.UPLVG alginate was selected as a starting material for modificationexperiments. In the first combinatorial reaction, the unmodifiedalginate was reacted with one of the alcohols, amines, and amines usedto introduce an azide moiety in the presence of2-Chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and N-methyl morpholine(NMM). In a second combinatorial step, each of the modified alginatepolymers formed above was reacted with another of the alcohols, amines,or amines used to introduce an azide moiety in the presence of2-Chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and N-methyl morpholine(NMM). In a final combinatorial step, all members of the library whichwere reacted with an amine used to introduce an azide moiety werefurther functionalized using a 1,3-dipolar cycloaddition reaction. Thosemembers of the library which had been reacted with 4-iodobenzylaminewere first reacted with sodium azide to convert the iodide moieties toazide moieties. Subsequently, all members of the library which werereacted with an amine used to introduce an azide moiety were reactedwith one of the alkynes used as reagents for 1,3-dipolar cycloadditionin the presence of CuSO₄/sodium ascorbate.

To optimize the biocompatibility of the chemically modified alginates, arigorous purification methodology was developed to eliminate potentiallyirritating impurities. Following each covalent modification, themodified alginates were filtered through a cyano-modified silica columnaimed at capturing bulk organic impurities. Finally, after completingall covalent modification steps, the modified alginates were dialyzedagainst 10,000 MWCO membrane to remove any remaining small-molecule orlow molecular weight impurities.

The purity of the modified alginates was determined by ¹H NMR analysis.The ¹H NMR spectra of each modified alginate polymer was collected, andpeaks corresponding to the modified alginate polymer and to anyimpurities were integrated to determine the relative quantity of eachspecies in the sample.

Example 2: High Throughput Screening of Modified Alginates Using aHydrogel Formation Assay

Covalent modification of the alginates affects the physical propertiesof the alginate, including the ability of the alginate to form hydrogelssuitable for the encapsulation of cells and biomolecules. To eliminatemodified alginates that have lost their ability to form hydrogels and tofurther focus our screening efforts on stronger candidates, afluorescence-based crosslinking assay was used to quantify the abilityof modified alginates to form hydrogels.

The hydrogel formation assay described herein exploits the ability ofhydrogels to trap fluorescent compounds, and differentially retain thefluorophores upon washing based on the stability of the hydrogel. Eachof the modified alginates prepared using the combinatorial approachdescribed in Example 1 was dissolved in water. A rhodamine dye thatfluoresces at 580 nm was added to each sample. The modified alginatesample was then crosslinked by the addition of a barium or calcium salt,for example BaCl₂, to induce formation of a hydrogel. After incubationfor 10 minutes, each sample was washed repeatedly with water. Thefluorescence intensity of each sample was measured using a fluorimeter.

Each modified alginate was screened three times, and the resultsobtained in the three trials were averaged. The average fluorescenceintensity values for each modified alginate were compared to thefluorescence levels of the negative control (water) and unmodifiedalginate (UPLVG). Modified alginates yielding fluorescence values belowthe negative control were considered unusable for applications wherehydrogel formation is critical (i.e. the encapsulation of cells).

Example 3: In Vitro Screening of Modified Alginates for Biocompatibility

The cytotoxicity of the modified alginate polymers on HeLa cells wasevaluated to screen for biocompatibility in vitro. The modifiedalginates identified in Example 2 as capable of forming hydrogels wereloaded into wells of 96-well plates which were coated withpoly-L-lysine. Unmodified alginate and saline were also loaded intowells of 96-well plates which were coated with poly-L-lysine ascontrols. A 100 mM BaCl₂ crosslinking solution was dispensed in all ofthe wells of the 96-well plate. The excess crosslinker was thenaspirated. HeLa cells were seeded into the wells and incubated for 3days at 37° C. in a humidified chamber.

A cell viability assay using3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) wasperformed, in which the media was aspirated from all wells and 100 μl ofDMEM media without phenol red and 10 μl MTT (5 mg/ml) were added to allof the wells of the 96-well plate. The plate was incubated for 4 hoursat 37° C. in a humidified chamber. After incubation, 85 μl of solutionwas aspirated and 100 μl DMSO was added. Purple formazan crystals formduring the assay in proportion to the number of viable HeLa cellspresent in each well. The contents of each well were pipetted up anddown to solubilize the formazan crystals prior to measurement. The platewas incubated at 37° C. for 10 minutes after which the bubbles fromagitation were removed. The plate was read using a UV/Vis plate readerat 540 nm with a reference at 700 nm. The viability was normalized tocells seeded in wells with no alginate.

The results of the cell viability are shown in FIG. 3, which plots theeffect of selected modified alginates on HeLa cell line viability ascompared to the positive control (no alginate). Alginate (Alg) has aviability of 53%. The assay identified modified alginate polymers whichdisplayed decreased cytotoxicity relative to unmodified alginate. Thesewere selected for further analysis.

Example 4: High Throughput In Vivo Screening of Modified Alginates toAssess Biocompatibility

Current biocompatibility analysis methods are slow and requirehistological analysis. In order to screen the large numbers of modifiedalginates prepared using the combinatorial synthetic methods describedherein, a high throughput in vivo biocompatibility assay was used toassess the relative biocompatibility of alginate polymers.

I. High Throughput In Vivo Screening Protocol

8-12 week old male SKH1 mice were obtained from Charles RiverLaboratories (Wilmington, Mass.). The mice were maintained at the animalfacilities of Massachusetts Institute of Technology, accredited by theAmerican Association of Laboratory Animal care, and were housed understandard conditions with a 12-hour light/dark cycle. Both water and foodwere provided ad libitum.

Injections were performed in accordance with ISO 10993-6: 2001. Prior toinjection all materials were sterilized via 0.22 μm filtration. The micewere anesthetized via isoflurane inhalation at a concentration of 1-4%isoflurane/balance O₂ to minimize movement. Their backs were scrubbedwith 70% isopropyl alcohol and the animals were injected with modifiedalginates in an array format on the animals' back for high-throughputscreening. Six injections were made in each mouse with one of theinjections being an unmodified alginate control. Injection volumes were100 μl.

On days 1, 3, 7, 14, 21, and 28 post-injection, host cell activity inresponse to the implantation of modified alginates was imagedkinetically using fluorescent whole animal imaging. 24 hours before invivo fluorescence imaging, 2 nmol of ProSense-680 (VisEn Medical,Woburn, Mass., excitation wavelength 680±10 nm, emission 700±10 nm)dissolved in 150 μl sterile PBS was injected into the tail vein of eachmouse to image cathepsin activity.

In vivo fluorescence imaging was performed with an IVIS-Spectrummeasurement system (Xenogen, Hopkinton, Mass.). The animals weremaintained under inhaled anesthesia using 1-4% isoflurane in 100% oxygenat a flow rate of 2.5 L/min. A binning of 8×8 and a field of view of13.1 cm were used for imaging. Exposure time and f/stop—the relativesize of the opening of the aperture—were optimized for each acquiredimage. Data were acquired and analyzed using the manufacturer'sproprietary Living Image 3.1 software. All images are presented influorescence efficiency, which is defined as the ratio of the collectedfluorescent intensity to an internal standard of incident intensity atthe selected imaging configuration. Regions of interest (ROIs) weredesignated around the site of each injection.

Biocompatibility of the materials was examined 14 days post injection.The fluorescence intensity measured at the implantation site of modifiedalginates was compared with the fluorescence intensity measured at theimplantation site of and unmodified alginates. Modified alginatesexhibiting smaller fluorescence intensity at the implantation site thanthe fluorescence intensity measured at the implantation site ofunmodified alginates were characterized as biocompatible. Modifiedalginates exhibiting greater fluorescence intensity at the implantationsite than the fluorescence intensity measured at the implantation siteof unmodified alginates were characterized as not biocompatible.

The in vivo stability of the alginate gels was assessed at 28 days postinjection. Modified alginates which remained at the site of injectionafter 28 days were characterized as capable of forming mechanicallystable hydrogels in vivo. Modified alginates which were not present atthe site of injection after 28 days were deemed to not capable offorming mechanically stable hydrogels in vivo, and were classified as‘failures’.

Modified alginates characterized as both biocompatible and capable offorming mechanically stable hydrogels in vivo were identified as ‘hits’,and selected for further study.

2. Validation of the High Throughput In Vivo Screening Protocol

In order to validate the high throughput in vivo screening assaydescribed above, modified alginates were subcutaneously injected intomice in an array format and crosslinked in situ as described above. Micewere imaged on days 1, 3, 7, 14, 21, and 28 post-injection usingfluorescent, whole animal imaging, and tissue samples were collectedafter imaging for histological analysis. To obtain tissue samples forhistological analysis, mice were euthanized via CO₂ asphyxiation and theinjected biomaterial and surrounding tissue were excised. The tissueswere then fixed in 10% formalin, embedded in paraffin, cut into 5 μmsections, and stained using hematoxylin and eosin (H&E) for histologicalanalysis by a board certified pathologist.

Fibrosis was rated on a scale where a zero involved no fibrosis, a oneindicated partial coverage with one to two layers of fibrosis, a two isdesignated a thicker fibrotic layer that nearly covered the implant, anda three denoted concentric fibrotic coverage of the polymer. Bothpolymorphonuclear (PMN) cells and macrophages were rated on a scalewhere no observed cells were indicated with a zero, scattered cellsscored a one, numerous cells clustering on the sides of the polymerscored a two, and numerous cells surrounding the material resulted in athree. Both the histological score and fluorescence response normalizedto alginate were examined for the whole library and materials thatoutperformed unmodified alginate were judged to be biocompatible. Thiscorresponds to a normalized fluorescent signal of <100% and a fibrosisscore of <3.

Data captured using whole animal imaging was demonstrated to displayedsimilar temporal trends in cellular recruitment of phagocytes to thebiomaterials compared to histological analysis. Accordingly, the highthroughput in vivo screening method described above was validated.

Example 5: In Vivo Screening of Modified Alginates to QuantifyBiocompatibility

8-12 week old male SKH1 mice were obtained from Charles RiverLaboratories (Wilmington, Mass.). The mice were maintained at the animalfacilities of Massachusetts Institute of Technology, accredited by theAmerican Association of Laboratory Animal care, and were housed understandard conditions with a 12-hour light/dark cycle. Both water and foodwere provided ad libitum.

Injections were performed in accordance with ISO 10993-6: 2001. Prior toinjection all materials were sterilized via 0.22 μm filtration. The micewere anesthetized via isoflurane inhalation at a concentration of 1-4%isoflurane/balance O₂ to minimize movement. Their backs were scrubbedwith 70% isopropyl alcohol and the animals were injected with a modifiedalginate. The injection volume was 100 μl.

Cathepsin activity was measured 7 days post injection using an in vivofluorescence assay to quantify the foreign body response to the modifiedalginate. 24 hours before in vivo fluorescence imaging, 2 nmol ofProSense-680 (VisEn Medical, Woburn, Mass., excitation wavelength 680±10nm, emission 700±10 nm) dissolved in 150 μl sterile PBS was injectedinto the tail vein of each mouse to image cathepsin activity.

In vivo fluorescence imaging was performed with an IVIS-Spectrummeasurement system (Xenogen, Hopkinton, Mass.). The animals weremaintained under inhaled anesthesia using 1-4% isoflurane in 100% oxygenat a flow rate of 2.5 L/min. A binning of 8×8 and a field of view of13.1 cm were used for imaging. Exposure time and f/stop—the relativesize of the opening of the aperture—were optimized for each acquiredimage. Data were acquired and analyzed using the manufacturer'sproprietary Living Image 3.1 software. All images are presented influorescence efficiency, which is defined as the ratio of the collectedfluorescent intensity to an internal standard of incident intensity atthe selected imaging configuration. Regions of interest (ROIs) weredesignated around the site of each injection.

Fluorescence images were captured 7 days post-injection illustratingrelative cathepsin activity at the point of injection of selectedmodified alginates. The fluorescence intensity was measured andnormalized to the fluorescence response measured using unmodifiedalginate in order to quantify the biocompatibility of the modifiedalginates. The results obtained for selected modified alginates areincluded in FIG. 4.

Example 6: Treatment of Diabetes in STZ-Induced Diabetic Mice

The transplantation of biocompatible alginate-encapsulated beta cellsoffers potential as a treatment for diabetes. Pancreatic rat islet cellswere encapsulated using fourteen biocompatible modified alginatepolymers identified using the assays detailed above (includingPF_N287_B_B4, PF_N287_F2, PF_N287_G3, PF_N287_B3, PF_N287_B_B8,PF_N287_A4, PF_N287_B1, PF_N287_E3, PF_N263_C12, PF_N63_A12, PF_N287_E1,PF_N287_D3, PF_N263_A7, and PF_N263_C6). Alginate-encapsulated isletscapsules were fabricated from 750 μl of a 4% (w/v) solution of eachmodified alginate in deionized water containing suspended 1,000 isletssuspended using the Inotech encapsulator (Inotech) set to a voltage of1.05 kV, a vibration of 1225 Hz, and a flow rate of 10-25 ml/min with a300 μm nozzle. Alginate was crosslinked in a 20 mM BaCl₂ solution. Afterencapsulation, the capsules were washed twice with HEPES solution, fourtimes with Krebs solution, and twice with RPMI-1640 medium.

The encapsulated rat islet cells were transplanted into STZ induceddiabetic mice. Prior to transplantation, the mice were anesthetizedunder continuous flow of 1-4% isofluorane with oxygen at 0.5 L/min. Ashaver with size #40 clipper blade will be used to remove hair to revealan area of about 2 cm×2 cm on ventral midline of the animal abdomen. Theentire shaved area was aseptically prepared with a minimum of 3 cyclesof scrubbing with povidine, followed by rinsing with 70% alcohol. Afinal skin paint with povidine was also applied. The surgical site wasdraped with sterile disposable paper to exclude surrounding hair fromtouching the surgical site. A sharp surgical blade was used to cut a0.5-0.75 cm midline incision through the skin and the linea alba intothe abdomen. A sterile plastic pipette was used to transfer the alginatecapsules into the peritoneal cavity. The abdominal muscle was closed bysuturing with 5-0 Ethicon black silk or PDS-absorbable 5.0-6.0monofilament absorbable thread. The external skin layer was closed usingwound clips. These wound clips were removed 7-10d post-surgery aftercomplete healing was confirmed.

Blood glucose levels in the STZ induced diabetic mice were monitoreddaily for between 20 and 30 days post-transplantation using a drop ofblood obtained by scrubbing the tail with 70% isopropyl alcohol andmaking a superficial cut on the skin of the tail to produce a drop ofblood. Mice were restrained during sampling in a rotating tail injector.

The blood glucose levels in the STZ induced diabetic mice followingislet transplantation are shown in FIG. 5. The dashed black linerepresents normoglycemia in mice. Pancreatic rat islet cells that wereencapsulated in modified alginates were able to reduce the blood glucoselevels in all cases, and in some cases, were even able to inducenormoglycemia.

Example 7: Particles Prepared from Mixture of Modified Alginate(s) andUnmodified Alginate

The growing recognition of the parameters driving fibrosis in vivo hasbeen applied to the analysis of the performance of modified alginates.Intraperitoneal (IP) implantation of modified alginate capsules revealedthat modified alginates may result in abnormally shaped capsules whencrosslinked using conditions defined for unmodified alginates. Theseabnormally shaped capsules can complicate implementation andinterpretation of modified alginate capsules implanted IP. In an effortto improve the capsule morphology, formulation methods for use withmodified alginate microparticles were developed where modified alginateswere blended with a small amount of high molecular weight alginate.Particles prepared from this mixture yielded particles with improvedmorphology and stability.

A 6% solution of modified alginate (w/w) was combined 1:1 by volume witha 1.15% solution of unmodified alginate (w/w). After mixing, capsulesare formed by following this solution through an electrostatic dropletgenerator, followed by crosslinking of the polymer in a 20 mM aqueousbarium chloride solution.

Particles prepared from modified alginate 263_A12 microparticlesformulated with barium and mannitol were compared to particles preparedfrom 263_A12 blended with a small amount of unmodified SLG100 alginate(16% by weight). The particles prepared from a mixture of modifiedalginate and unmodified alginate produced more homogenous microparticlepopulations. Quantitative fluorescence analysis with prosense at severaltime points with modified alginates blended with SLG100 was performed.The results are shown in FIG. 6. Several reformulated modified alginatesdisplayed less inflammatory response at day 7 compared to the controlalginate. Initial experiments with large capsules (1.5 mm diameter) showcomparably clean capsules after 2 weeks in the IP space ofimmunocompetent C57BL6 mice.

Data collected to date with these controlled capsules indicates thatreformulation and capsule morphology can have a significant effect oninflammation as measured by prosense. An improved inflammation responseis observed in some polymers (FIG. 6), while others are impactednegatively.

Example 8: Demonstration of Anti-Fibrotic Activity of Modified Alginates

In this example, a chemical modification approach was taken to mitigatethe immune recognition of alginate microspheres in preclinical fibrosismodels, including NHPs, which are relevant to translation in humans. Thelead materials evade immune recognition and fibrosis in the IP space ofboth C57BL/6 mice and cynomolgus macaques. This alginate blocksmacrophage adhesion, stunting activation of the foreign body responseand providing insight to the surface properties necessary to overcomethe fibrosis of implanted materials.

I. Methods

A. Alginate Chemical Modification

I. Alginate Amidation

Alginate (Pronova UPVLVG from NovaMatrix, 1 eq., 100 mg=0.52 mmol ofCOOH available for reaction) was dissolved as a 2% Alginate solution ina 3:2 water:acetonitrile mixture (5 ml total volume). Amine (N1 to N9,Z1, Z2) (1 eq, Sigma Aldrich or TCI America) was then added to themixture along with the coupling agent2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT, 0.5 eq., 45 mg, SigmaAldrich) and 4-Methylmorpholine (NMM, 1 eq., 56 μl, Sigma Aldrich). Themixture was stirred at 55° C. overnight and the solvent was removedunder reduced pressure. The resulting solid was dissolved in water andfiltered through cyano modified silica gel (Silicycle) to removeinsoluble precipitate. The resulting solution was then dialyzed againsta 10,000 MWCO dialysis membrane overnight with DI water to furtherpurify the polymer. The resulting solution was then lyophilized to getpurified compound.

2. Alginate Esterification

Alginate (Pronova UPVLVG from NovaMatrix, 1 eq., 100 mg=0.52 mmol ofCOOH available for reaction) was dissolved as a 2% Alginate solution ina 3:2 water:alcohol (O1 to O12) mixture (5 ml total volume). Thecoupling agent 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT, 0.5 eq., 45mg, Sigma Aldrich) and 4-Methylmorpholine (NMM, 1 eq., 56 μl, SigmaAldrich) was then added and the mixture was stirred at 55° C. overnight.The next day the solvent was removed under reduced pressure. Theresulting solid was dissolved in water and filtered through cyanomodified silica gel (Silicycle) to remove insoluble precipitate. Theresulting solution was then dialyzed against a 10,000 MWCO dialysismembrane overnight with DI water to further purify the polymer. Theresulting solution was then lyophilized to get purified compound.

3. Huisgen Cycloaddition (“Click”)

In a second step, alginates reacted with Z2 were dissolved in a solutionof water: methanol 1:1 (5 ml total). Sodium azide (0.25 eq., 19 mg,Sigma Aldrich), sodium L-ascorbate (0.05 eq., 19 mg, Sigma Aldrich),trans-N,N′-Dimethylcyclohexane-1,2-diamine (0.25 eq., typically 20 μl,Sigma Aldrich), Copper(I)-Iodide (0.5 eq., 10 mg, Sigma Aldrich) wereadded as coupling agents. Then 0.51 mmol of the respective Alkyne (Y1 toY20) was added and the mixture was stirred at 55° C. overnight. Thesolvent was removed under reduced pressure. The resulting solid wasdissolved in water and filtered through cyano modified silica gel toremove insoluble precipitate. The clear solution was lyophilized anddissolved in 5 ml of water and dialyzed. The resulting solution was thendialyzed against a 10,000 MWCO dialysis membrane overnight with DI waterto further purify the polymer. The resulting solution was thenlyophilized to get purified compound.

In a second step, alginates reacted with Z1 were dissolved in a solutionof water: methanol 1:1 (5 ml total).Tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA, 0.2 eq., 50 mg,Sigma Aldrich), Trietylamine (0.25 eq., typically 15 μl, Sigma Aldrich),Copper(I)-Iodide (0.25 eq., 5 mg, Sigma Aldrich) were added as couplingagents. Then 0.51 mmol of the respective Alkyne was added and themixture was stirred at 55° C. overnight. The solvent was removed underreduced pressure. The resulting solid was dissolved in water andfiltered through cyano modified silica gel to remove insolubleprecipitate. The clear solution was lyophilized, dissolved in 5 ml ofwater and dialyzed. The resulting solution was then dialyzed against a10,000 MWCO dialysis membrane overnight with DI water to further purifythe polymer. The resulting solution was then lyophilized to get purifiedcompound.

4. Optimized syntheses for preparation of Z2-Y12, Z1-Y15 and Z1-Y19:

Z2-Y12 Amine:

10 g of 2-(2-Propynyloxy) tetrahydopyran (1 eq. 71.36 mmol) was added toa solution of 5.1 g Sodium azide (1.1 eq, 78.5 mmol), 1.41 g Sodiumascorbate (0.1 eq, 7.14 mmol), 2.29 mlTrans-N—N′-Dimethylcyclohexane-1,2-diamine (0.25 eq, 17.83 mmol), 3.4 gCopper(I)-iodide (0.025 eq, 17.83 mmol) in 75 ml methanol. To thismixture 19.97 g of 4 Iodobenzylamide HCl was added. The reaction wasstirred overnight at 55° C. The solvent was removed under reducedpressure. The crude reaction was purified by liquid chromatography withdichloromethane:ultra (22% MeOH in DCM with 3% NH₄OH) mixture 0%->40% onsilica gel. The product was then reacted with alginate as describedbelow.

Z1-Y15 Amine:

3.5 g of 4-Propagylthiomorpholine 1,1-Dioxide (1 eq. 20 mmol) was addedto a solution of 2.5 g TBTA (0.2 eq, 4 mmol), 750 μl Triethylamine (0.5eq, 10 mmol), 250 mg Copper(I)-iodide (0.06 eq, 1.3 mmol) in 50 mlmethanol. The mixture was cooled to 0° C. and 5.25 ml of11-Azido-3,6,9-trioxaundecan-1-amine (1 eq, 20 mmol) was added. Thereaction was stirred overnight at 55° C. The solvent was removed underreduced pressure. The crude reaction was purified by liquidchromatography with dichloromethane:ultra (22% MeOH in DCM with 3%NH₄OH) mixture 0%->100% on a C18 column. The product was then reactedwith alginate as described below.

Z1-Y19 Amine:

3 g of 4-Ethynylaniline (1 eq. 20.2 mmol) was added to a solution of 2.5g TBTA (0.2 eq, 4 mmol), 750 μl Triethylamine (0.5 eq, 10.1 mmol), 250mg Copper(I)-iodide (0.06 eq, 1.31 mmol) in 50 ml methanol. The mixturewas cooled to 0° C., and 5.25 ml of 11-Azido-3,6,9-trioxaundecan-1-amine(1 eq, 20 mmol) was added. The reaction was stirred overnight at 55° C.The solvent was removed under reduced pressure. The crude reaction waspurified by liquid chromatography with dichloromethane:ultra (22% MeOHin DCM with 3% NH₄OH) mixture 0%->30% on a cyano functionalized silicacolumn. The product was then reacted with alginate as described below.

Alginate Reaction:

1.5 g of UPVLVG (1 eq) was dissolved in 45 ml of water and 675 mg of2-Chloro-4,6-dimethoxy-1,3,5-triazine (CDMT, 0.5 eq) and 840 μl ofN-Methylmorpholine (NMM, 1 eq) was added. Then 7.65 mmol of the Z2-Y12,Z1-Y15, or Z1-Y19 amine was dissolved in 22.5 ml acetonitrile and addedto the mixture. The reaction was stirred overnight at 55° C. The solventwas removed under reduced pressure and the solid was dissolved in water.The solution was filtered through a pad of cyano functionalized silicaand the water was removed under reduced pressure to concentrate thesolution. It was then dialyzed against a 10,000 MWCO membrane in DIwater overnight. The water was removed under reduced pressure to givethe functionalized alginate.

B. Capsule Formation

An electrostatic droplet generator was set up as follows: an ES series0-100 KV, Watt high voltage power generator (Gamma ES series, Gamma HighVoltage Research, FL, USA) is connected to the top and bottom of a blunttipped needle (SAI Infusion Technologies, IL, USA). This needle isattached to a 5 mL lure lock syringe (BD, NJ, USA) which is clipped to asyringe pump (Pump 11 Pico Plus, Harvard Apparatus, MA, USA) that isoriented vertically. The syringe pump pumps alginate out into a glassdish containing a 20 mM barium 5% mannitol solution (Sigma Aldrich, MO,USA). The settings of the PicoPlus syringe pump are 12.06 mm diameterand 0.2 mL/min flow rate. After the capsules are formed, they are thencollected and then washed with hepes buffer (NaCl 15.428 g, KCl 0.70 g,MgCl2*6H2O 0.488 g, 50 mL of hepes (1M) buffer solution (Gibco, LifeTechnologies, California, USA) in 2 L of DiH2O) 4 times. The alginatecapsules are left overnight at 4° C. The capsules are then washed 2times in 0.8% saline and kept at 4° C. until use.

Solubilizing alginates: SLG20 (NovaMatrix, Sandvika, Norway) wasdissolved at 1.4% weight to volume in 0.8% saline. SLG100 (NovaMatrix,Sandvika, Norway) was dissolved at 1.2% weight to volume in 0.8% saline.UPVLVG (NovaMatrix, Sandvika, Norway) was dissolved at 5% weight tovolume in 0.8% saline. All modified alginates were initially dissolvedat 5% weight to volume in 0.8% saline. Modifies were then blended with3% weight to volume SLG100, dissolved in 0.8% saline (see Table 3 forratios).

Forming different sized capsules: for 300 μm diameter capsules, a 30gauge blunt tipped needle (SAI Infusion Technologies) was used with avoltage of 7-8 kV. For 500 μm diameter capsules, a 25 gauge blunt tippedneedle (SAI Infusion Technologies) was used with a voltage of 5-7 kV.For 1.5 mm capsules, an 18 gauge blunt tipped needle (SAI InfusionTechnologies) was used with a voltage of 5-7 kV.

TABLE 3 Modified Alginate to SLG100 blended volume ratios % Volume %Modified Modified Volume Alginate Solution SLG100 361_E9 70 30 411_RN880 20 411_OH6 60 40 411_OH9 60 40 411_OH11 50 50 411_OH3 80 20 411_RZA1580 20 411_RZA2 50 50 411_RZA19 70 30 411_RN7 80 20 VLVG/SLG100* 80 20Table 3 Legend: Modified alginates are blended with SLG100 to makecapsules. Modified alginate and SLG100 are drawn into a 5 mL syringe andthoroughly vortexed before encapsulation. Different modified alginatesrequire a different percent volume of SLG100 added to make sphericalcapsules. *VLVG/SLG100 is a control blend. The unmodified VLVG isblended with SLG100.

C. Transplantation of the Hydrogel Capsules and Other Material Spheres

All animal protocols were approved by the MIT Committee on Animal Care,and all surgical procedures and post-operative care was supervised byMIT Division of Comparative Medicine veterinary staff. Immune-competentmale C57BL/6 mice (Jackson Laboratory, Bar Harbor, Me.) wereanesthetized with 3% isoflurane in oxygen and had their abdomens shavedand sterilized using betadine and isopropanol. A 0.5 mm incision wasmade along the midline of the abdomen and the peritoneal lining wasexposed using blunt dissection. The peritoneal wall was then graspedwith forceps and a 0.5-1 mm incision was made along the linea alba. Adesired volume of capsules were then loaded into a sterile pipette andtransplanted into the peritoneal cavity through the incision. Theincision was then closed using 5-0 taper tipped polydioxanone (PDS II)absorbable sutures. The skin was then closed over the incision using awound clip and tissue glue. Preoperatively, all mice also received a0.05 mg/kg dose of buprenorphine subcutaneously as a pre-surgicalanalgesic, along with 0.3 mL of 0.9% saline subcutaneously to preventdehydration.

D. Retrieval of Cells, Tissues, and Materials

At desired time points post-transplantation, as specified in figures andresults, mice were euthanized by CO₂ administration, followed bycervical dislocation. In certain instances, 5 ml of ice cold PBS wasfirst injected in order perform an intraperitoneal lavage to rinse outand collect free-floating intraperitoneal immune cells. An incision wasthen made using the forceps and scissors along the abdomen skin andperitoneal wall, and intraperitoneal lavage volumes were pipetted outinto fresh 15 ml falcon tubes (each prepared with 5 ml of RPMI cellculture media). Next, a wash bottle tip was inserted into the abdominalcavity. KREBS buffer was then used to wash out all material capsulesfrom the abdomen and into petri dishes for collection. After ensuringall the capsules were washed out or manually retrieved, if fibroseddirectly to intraperitoneal tissues, they were transferred into 50 mLconical tubes for downstream processing and imaging. Afterintraperitoneal lavage and capsule retrieval, remaining fibrosedintraperitoneal tissues were also excised for downstream FACS andexpression analyses.

E. Imaging of the Retrieved Material Capsules

For phase contrast imaging, retrieved materials were gently washed usingKrebs buffer and transferred into 35 mm petri dishes for phase contrastmicroscopy using an Evos X1 microscope (Advanced Microscopy Group).

F. ProSense Assay

Female SKH1 mice (6 weeks old) were utilized for this assay. 100 ul ofcapsules were resuspended in 200 ul of saline, and injectedsubcutaneously into the mouse on the left side of upper back. The micewere feeded on AIN-93G purified rodent diet (TD 94045, Harlan) tominimize the fluorescent background after injection. Six days later, 100ul (4 nmol) of ProSence 750 FAST (NEV11171, PerkinElmer Inc.) per mousewas injected intravenously via tail vein. At day 7 (i.e., 24 hours postthe ProSense 750 FAST intravenous administration), the mice were scannedby IVIS Spectrum system (Xenogen, Caliper LifeScience). The mice wereanesthetized using 3% isofluorane in oxygen and maintained at the samerate throughout the procedure, and the settings of the IVIS Spectrumsystem were Exposure=7.50, Binning=Medium, FStop=2, Excitation=605 andEmission=660. The images were analyzed with LivingImage Software, andthe right side of upper back on the same mouse was used as controlduring the signal quantification.

G. Cell Staining and Confocal Immunofluorescence

Retrieved samples were stored in 4% paraformaldehyde overnight (dilutedin 1×PBS). Samples were then washed in Krebs Buffer (7.889 g NaCl, 0.35g KCl, 5.958 g HEPES (Sigma-Aldrich, Montana, USA), 0.163 g KH2PO4,0.144 g MGSO4*7H2O in 1000 mLs of DiH2O). Samples were washed with 10mLs of PBS. PBS was aspirated and 20 mL of 1% Triton X-100(Sigma-Aldrich, Montana, USA) solution was used to permeabilize cells.Samples were incubated for 10 minutes at room temperature. Samples werethen incubated in 15 mLs of 1% albumin solution (Sigma-Aldrich, Montana,USA), diluted in 1×PBS for 30 minutes at room temperature. 3 mLs ofantibody solution (1:200 CD68488 Anti Mouse (BioLegend California, USA),1:200 Anti-Mouse Actin, α-Smooth Muscle-Cy3(Sigma-Aldrich, Montana,USA), 1:30 Phalloidin anti mouse 647 (Life Technologies, California,USA), DAPI (NucBlue Live Cell Stain ReadyProbes, Life Technologies,California, USA) 2 drops per mL) all diluted in 1% albumin solution wasadded to each sample. Samples were incubated in staining solution for 45minutes at room temperature. Staining solution was then aspirated.Samples were then washed twice with 20 mLs of 0.1% tween 20 solution(Sigma-Aldrich, Montana, USA), diluted in 1×PBS. Samples were thenwashed twice with 20 mLs of 1×PBS. Samples were then transferred to a 24well glass bottom plate. Excess PBS was aspirated and 1 mL of 50%glycerol solution (Sigma-Aldrich, Montana, USA) was added. A Zeiss LSM700 system with ZEN microscope software was used to image and analyzethe stained samples. Obtained images where adjusted linearly forpresentation using Photoshop (Adobe Inc. Seattle, Wash.).

H. Protein Extraction

Cells on retrieved capsules were lysed by sonication for 30 seconds on30 seconds off cycle three times at 70% amplitude (QSonica Sonicator,Model #Q125, QSonica LLC) on ice in NP40 cell lysis buffer (Cat#FNN0021, Invitrogen) at the ratio of 100 ul capsules to 200 ul lysisbuffer, with 100 mM PMSF and 1× protease inhibitors (Halt Proteaseinhibitor single-use cocktail, Cat. #78430, Thermo Scientific). Lysateswere centrifuged for 20 min at 12000 rpm at 4° C.; the supernatant whichcontains proteins was aspirated in a fresh tube kept on ice. The pelletswere washed with the same volume of lysis buffer (i.e. the pellet of 100ul capsules were washed with 200 ul lysis buffer), and then centrifugedfor 20 min at 12000 rpm at 4° C., combined the supernatant with theprevious one. The proteins were stored at −80° C. for future use.

I. Elispot (Mouse Cytokine Array)

This assay was accomplished with Proteome Profiler Mouse Cytokine ArrayPanel A kit (Cat #ARY006, R&D system). For each membrane, 200 ul ofprotein solution was mixed with 100 ul of sample buffer (array buffer 4)and 1.2 ml of block buffer (array buffer 6), then added with 15 ul ofreconstituted Mouse Cytokine Array Panel A Detection Antibody Cocktailand incubated at room temperature for 1 hour. The array membrane wasincubated with block buffer (array buffer 6) for 2 hours on a rockingplatform shaker in the meantime, and then the block buffer wasaspirated, the prepared sample/antibody mixture was added onto themembrane and incubated overnight at 4° C. on a rocking platform shaker.The membrane was washed with 20 ml of 1× wash buffer for 10 minutes on arocking platform shaker for three time and rinsed with deionized wateronce, then was probed with Fluorophore-conjugated streptavidin (1:5,000dilution, Cat #926-32230, Li-Cor) at room temperature for 30 minutes ona rocking platform shaker, washed with wash buffer for three times andrinsed with deionized water once again as in above steps.Antibody-antigen complexes were visualized using Odyssey Detection(Li-Cor, Serial No. ODY-2329) at 800 nm wavelengths. The densities ofthe spots were analyzed by Image J software.

J. Western Blotting

12 ul of protein solution mixed with 1× loading buffer (SDS-Samplebuffer, Cat. #BP-111R, Boston BioProducts) for each lane was boiled at95° C. for 20 min and electrophoresed on SDS polyacrylamide gels (Any Kd15-well comb mini-gel, Biorad, Cat #456-9036), and 3 ul of PrecisionPlus Protein Dual Xtra Stands (Cat #161-0377, Bio-rad) was used asladder to indicate the position of the bands, and then blotted ontonitrocellulose membranes (Biorad, Cat. #162-0213). Blots were probedwith anti-αSmooth Muscle actin antibody (1:400 dilution, Rabbitpolyclonal to alpha smooth muscle Actin; Cat. #ab5694, AbCam) andanti-βactin antibody (1:4000 dilution, Monoclonal Anti-β-Actin antibodyproduced in mouse; Cat #A1978, Sigma Aldirch) as a loading controlfollowed by Donkey Anti-Rabbit (1 to 15,000 dilution, Cat #926-32213,Li-Cor) and Goat Anti-Mouse (1 to 15,000 dilution, Cat #926-68070,Li-Cor) Fluorophore-conjugated secondary antibodies. Antibody-antigencomplexes were visualized using Odyssey Detection (Li-Cor, Serial No.ODY-2329) at 700 and 800 nm wavelengths. The densities of the bands wereanalyzed by Image J software.

K. NanoString Analysis

RNAs for mock-transplanted (MT) controls, or for 500 or 1,500 μmalginate capsule-bearing mice (n=5/group) were isolated from tissuesamples taken at various time points after transplantation. RespectiveRNAs were quantified, diluted to the appropriate concentration (100ng/μl), and then 500 ng of each sample was processed according toNanoString manufacturer protocols for expression analysis via ourcustomized multiplexed 53-gene mouse macrophage subtyping panel. RNAlevels (absolute copy numbers) were obtained following nCounter(NanoString Technologies Inc., Seattle, Wash.) quantification, and groupsamples were analyzed using nSolver analysis software (NanoStringTechnologies Inc., Seattle, Wash.).

L. FACS Analysis

Single-cell suspensions of freshly excised tissues were prepared using agentleMACS Dissociator (Miltenyi Biotec, Auburn, Calif.) according tothe manufacturer's protocol. Single-cell suspensions were prepared inPEB dissociation buffer (IX PBS, pH 7.2, 0.5% BSA, and 2 mM EDTA) andsuspensions were passed through 70 μm filters (Cat. #22363548, FisherScientific, Pittsburgh, Pa.). All tissue and material sample-derived,single-cell populations were then subjected to red blood cell lysis with5 ml of 1×RBC lysis buffer (Cat. #00-4333, eBioscience, San Diego,Calif., USA) for 5 min at 4° C. The reaction was terminated by theaddition of 20 ml of sterile IX PBS. The cells remaining werecentrifuged at 300-400 g at 4° C., and resuspended in a minimal volume(˜50 μl) of eBioscience Staining Buffer (cat. #00-4222) for antibodyincubation. All samples were then co-stained in the dark for 25 min at4° C. with two of the fluorescently tagged monoclonal antibodiesspecific for the cell markers CD68 (1 μl (0.5 μg) per sample;CD68-Alexa647, Clone FA-11, Cat. #11-5931, BioLegend), Ly-6G (Gr-1) (1μl (0.5 μg) per sample; Ly-6G-Alexa-647, Clone RB6-8C5, Cat. #108418,BioLegend), CD11b (1 μl (0.2 μg) per sample; or CD11b-Alexa-488, CloneM1/70, Cat. #101217, BioLegend). Two ml of eBioscience Flow CytometryStaining Buffer (cat. #00-4222, eBioscience) was then added, and thesamples were centrifuged at 400-500 g for 5 min at 4° C. Supernatantswere removed by aspiration, and this wash step was repeated two moretimes with staining buffer. Following the third wash, each sample wasresuspended in 500 μl of Flow Cytometry Staining Buffer and run througha 40 μm filter (Cat. #22363547, Fisher Scientific) for eventual FACSanalysis using a BD FACSCalibur (cat. #342975), BD Biosciences, SanJose, Calif., USA). For proper background and laser intensity settings,unstained, single antibody, and IgG (labeled with either Alexa-488 orAlexa-647, BioLegend) controls were also run.

M. Intravital Imaging

For intravital imaging, SLG20 hydrogels of 500 μm and 1500 μm sizes wereloaded with Qdot 605 (Life technologies, Grand Island, N.Y.) andsurgically implanted intoC57BL/6-Tg(Csflr-EGFP-NGFR/FKBP1A/TNFRSF6)2Bck/J mice as describedabove. After 7 days post transplantation, the mice were placed underisoflurane anesthesia and a small incision was made at the site of theoriginal surgery to expose beads. The mice were placed on an invertedmicroscope and imaged using a 25×, N.A. 1.05 objective on an OlympusFVB-1000 MP multiphoton microscope at an excitation wavelength of 860nm. Z-stacks of 200 μm (10 μm steps) were acquired at 2-minute intervalsfor time series of 20-45 minutes depending on the image. The mice werekept under constant isoflurane anesthesia and monitored throughout theimaging session. Obtained images were analyzed using Velocity 3D ImageAnalysis Software (Perkin Elmer, Waltham, Mass.).

N. Confocal Raman Spectroscopy

Sample Preparation: A drop of hydrogel capsules with buffer solution wasdried on the quartz coverslip (043210-KJ, Alfa Aesar). In order toremove the salt from dried buffer solution, a drop of distilled waterwas gently applied on top of the dried sample and immediately absorbedby a tissue. By doing that, dried hydrogel capsules are prepared forRaman mapping.

Instrumentation: A custom-built NIR confocal Raman microscopy system waspreviously reported (Kang et al., Combined confocal Raman andquantitative phase microscopy system for biomedical diagnosis. Biomed.Opt. Exp. 2(9):2484-2492 (2011); Kang et al., Measuring uptake dynamicsof multiple identifiable carbon nanotube species via high-speed confocalRaman imaging of live cells. Nano Letters 12(12):6170-6174 (2012)).Briefly, a 785 nm wavelength Ti: Sapphire laser (3900S, Spectra-Physics)was used for sample excitation. The collimated beam was filtered by aband pass filter (BPF, LL01-785-12.5, Semrock) and redirected to thedual axes galvanometer mirrors. High-speed XY scanning was performed bythe galvanometer mirrors (CT-6210, Cambridge Technology). A 1.2 NA waterimmersion objective lens (Olympus UPLSAPO60XWIR 60X/1.20) was used toboth focus the laser light onto the sample and to collect theback-scattered light. A piezo actuator combined with a differentialmicrometer (DRV517, Thorlabs) was used to perform the coarse and fineadjustments, respectively, of the sample focus. A flip mirror was placedafter the tube lens so that the sample focal plane from the incoherenttransmission source can be observed using a video camera with 75×magnification. The back-scattered Raman light from the sample passesthrough two dichroic mirrors (DM1: Semrock LPD01-785RU-25, DM2: SemrockLPD01-785RU-25×36×1.1) and was collected by a multi-mode fiber (ThorlabsM14L01). The collected signal was delivered to the spectrograph(Holospec f/1.8i, Kaiser Optical Systems) and detected by athermoelectric-cooled, back-illuminated and deep depleted CCD (PIXIS:100BR_eXcelon, Princeton Instruments). LabView 8.6 software (NationalInstruments), data acquisition board (PCI-6251, National Instruments)and MATLAB 2013 software (Mathworks) were used to control the system,acquire the data, and analyze the data.

Raman Spectroscopy Measurement: 60 mW of 785 nm laser power was focusedto a micron spot size and used to raster scan the hydrogel samples.30×30 spectra were acquired from 45 μm×45 μm area with an integrationtime 1.0 s/pixel. The total measurement time was approximately 15minutes.

Data Processing: Two Raman images are generated based on the intensitiesof two Raman bands. These Raman images are resized and overlaid as redand green colors on top of corresponding bright field image from thesame area.

II. Polymer and Compound Characterization

N7: ¹H (400 MHz; D₂O): 3.10-4.10 (m, alginate protons), 4.20 (2H, s,H₂N—CH₂-Ph), 4.40-5.20 (m, alginate protons), 7.41 (2H, m, Phenyl), 7.49(3H, m, Phenyl)

IR (ATR): 3234, 1579, 1465, 1407, 1368, 1078, 810, 692, 517.

N8: ¹H (400 MHz; D₂O): 3.00-3.20 (m, alginate protons), 3.60 (8H, m,ethoxy), 3.60-5.10 (m, alginate protons).

IR (ATR): 3233, 2927, 2358, 1591, 1405, 1318, 1022, 945, 810.

O3: ¹H (400 MHz; D₂O): 1.90-2.10 (m, 4H, Furfuryl), 3.23 (m, 2H,Furfuryl) 3.26-4.00 (m, alginate protons), 4.03 (3H, m,O—CH2-C[furfuryl]), 4.10-5.20 (m, alginate protons)

IR (ATR): 3202, 3070, 2344, 1711, 1594, 1398, 1021, 715, 549

O6: ¹H (400 MHz; D₂O): 3.60-4.52 (m, alginate protons), 4.59 (2H, m,O—CH2-C[furfuryl]), 4.6-5.2 (m, alginate protons), 6.45 (2H, m,CH—CH═CH-0 Furfuryl), 7.53 (1H, m, CH—CH═CH—O Furfuryl).

IR (ATR): 3232, 2360, 1614, 1410, 1028, 538.

O9: ¹H (400 MHz; D₂O): 0.20 (s, 9H, Furfuryl),) 3.10-5.20 (m, alginateprotons).

IR (ATR): 3310, 2939, 2360, 1592, 1406, 1316, 1081, 1020, 902, 770.

O11: ¹H (400 MHz; D₂O): 3.05-4.50 (m, alginate protons), 4.52 (2H, s,O—CH₂-Ph), 4.52-5.2 (m, alginate protons), 6.88 (2H, m, Phenyl), 7.26(2H, m, Phenyl).

IR (ATR): 3370, 3089, 1597, 1517, 1454, 1235, 1207, 989, 835, 801, 561.

Z1-Y2: ¹H (400 MHz; D₂O): 3.05-3.40 (m, alginate protons), 3.40-3.66(16H, m, ethoxy), 3.75 (3H, s, methoxy) 3.8-5.1 (m, alginate protons),7.19 (1H, m, Phenyl), 7.50 (1H, m, Phenyl), 7.94 (1H, m, Phenyl), 8.00(1H, m, Phenyl), 8.49 (1H, s, triazole).

IR (ATR): 3144, 2922, 1592, 1400, 1329 1019, 943.

Z1-Y15: ¹H (400 MHz; D₂O): 3.07 (4H, s, N—CH₂—CH₂—S), 3.17-3.40 (m,alginate protons), 3.46 (4H, s, N—CH₂—CH₂—S), 3.50-3.70 (16H, m,ethoxy), 3.7-5.2 (m, alginate protons), 8.08 (1H, s, triazole).

IR (ATR):3268, 2933, 2250, 1602, 1409, 1292, 1119, 1023, 946.

Z1-Y19: ¹H (400 MHz; D₂O): 3.05-3.40 (m, alginate protons), 3.40-3.66(16H, m, ethoxy), 4.4-5.1 (m, alginate protons), 6.96 (2H, m, Phenyl),7.63 (3H, m, Phenyl), 8.23 (1H, s, triazole).

IR (ATR): 3234, 2929, 2361, 1593, 1406, 1317 1024, 947, 810.

Z2-Y12: ¹H (400 MHz; D₂O): 1.57-1.78 (m, 6H, pyran), 3.10-4.40 (m,alginate protons), 4.48 (4H, m, pyran), 4.50-5.10 (m, alginate protons),7.56 (2H, m, Phenyl), 7.76 (3H, m, Phenyl), 8.51 (1H, s, triazole).

IR (ATR): 3235, 2933, 2111, 1592, 1405, 1290, 1023, 946.

N4-N2: ¹H (400 MHz; D₂O): 2.72 (s, 3H, N—CH₃ Dioxolane) 2.77 (s, 3H,N—CH₃ Benzyl), 3.36 (2H, d, N—CH₂-Dioxolane), 3.55-4.20 (m, alginateprotons), 4.22 (2H, m, N—CH₂-Ph), 4.50-5.10 (m, alginate protons), 5.19(1H, m, CH2-CH—O Dioxolane), 7.51 (5H, m, Phenyl).

IR (ATR): 3250, 2894, 1601, 1409, 1127, 1088, 1029, 946.

O3-O10: ¹H (400 MHz; D₂O): 1.60-2.20 (m, 4H, Tetrahydrofurfuryl),3.55-5.10 (m, alginate protons), 3.78 (2H, m, CH₂—CH₂-0Tetrahydrofurfuryl), 3.85 (3H, s, COO—CH₃), 4.13-4.30 (3H, m, N—CH₂—Tetrahydrofurfuryl).

IR (ATR): 3448, 2926, 2111, 1618, 1420, 1290, 1096, 948, 904.

N9-O8: ¹H (400 MHz; D₂O): 1.28 (m, 3H, N—CH₂—CH₃), 1.32 (m, 3H,O—CH₂—CH₃), 1.63 (m, 3H, N—CH₂—CH₂—CH₂—CH₂—OH) 1.74 (m, 3H,N—CH₂—CH₂—CH₂—CH₂—OH), 3.09-3.40 (m, 6H, CH₃—CH₂— N—CH₂—CH₂—CH₂—CH₂—OH),3.55-5.10 (m, alginate protons), 4.06 (m, 3H, O—CH₂—CH₃).

IR (ATR): 3422, 1709, 1655, 1611, 1474, 1395, 1042, 798.

Small Molecule Preparations:

Z2-Y12 Amine:

¹H (400 MHz; MeOD): 1.57 (m, 4H, pyran), 1.72 (m, 1H, pyran), 1.82 (m,1H, pyran) 3.58 (m, 1H, pyran), 3.87 (s, 1H, NH₂—CH₂-Ph), 3.92 (m, 1H,pyran), 4.68 (d, 1H, J=12 Hz, O—CH₂-triazole), 4.79 (m, 1H, O—CH—Opyran), 4.97 (d, 1H, J=12 Hz, O—CH₂-triazole), 7.54 (m, 2H, aromatic),7.80 (m, 2H, aromatic), 8.49 (s, 1H, triazole). ¹³C (400 MHz; MeOD):20.3 (CH₂ pyran), 26.5 (CH₂ pyran), 31.5 (CH₂ pyran), 46.1 (NH₂CH₂),61.0 (O—CH₂—C), 63.3 (CH₂-0 pyran), 99.5 (O—CH—O pyran), 121.6 (CHaromatic), 123.17 (CH triazole), 129.9 (CH aromatic), 137.1 (Cq-Naromatic), 144.9 (Cq-C aromatic), 146.9 (C triazole).

High resolution MS: M+1=289.1665+3.1 ppm.

Z1-Y15 Amine:

¹H (400 MHz; D₂O): 2.86 (2H, s, NH₂), 3.01 (4H, m, N—CH₂—CH₂—S), 3.10(4H, m, N—CH₂—CH₂—S), 3.55 (2H, t, J=5.2 Hz, NH₂—CH₂),3.61 (8H, m, PEG)3.85 (2H, s, Thiomorpholine-CH₂-Triazole), 3.90 (2H, t, J=5.2 Hz,N—CH₂—CH₂-0), 4.59 (t, 2H, J=5.2, N—CH₂—CH₂-0), 7.99 (1H, s, triazole).

¹³C (400 MHz; MeOH): 41.7 (NH₂—CH₂), 51.42 (N—CH₂), 51.48 (N—CH₂Thiomorpholine) 52.1 (S—CH₂ Thiomorpholine) 52.4(Thiomorpholine-CH₂-Triazole), 70.4-72.1 (m, PEG), 126.0 (CH triazole),144.5 (C triazole).

High resolution MS: M+1=392.1968-6.1 ppm.

Z1-Y19 Amine:

¹H (400 MHz; MeOD): 2.79 (t, 2H, J=5.2 Hz, NH₂—CH₂), 3.46 (t, 2H, J=5.2,NH₂—CH₂—CH₂), 3.53 (m, 4H, PEG), 3.61 (m, 4H, PEG), 3.91 (t, 2H, J=5.2,N—CH₂—CH₂-0), 4.58 (t, 2H, J=5.2, N—CH₂—CH₂-0) 6.76 (m, 2H, aromatic),7.54 (m, 2H, aromatic), 8.14 (s, 1H, triazole).

¹³C (400 MHz; MeOD): 41.6 (NH₂—CH₂), 51.4 (N—CH₂), 70.3-71.9 (m, PEG),116.4 (CH aromatic), 121.1 (Cq-C), 121.5 (CH triazole), 127.7 (CHaromatic), 149.4 (C—NH₂ aromatic), 149.5 (C triazole).

High resolution MS: M+1=336.2036-8.3 ppm.

III. Results

The amines and alcohols listed in Table 4 were used to prepare themodified alginates. In the first combinatorial reaction, UPLVG alginatewas reacted with one of the compounds in Table 4 in the presence of2-Chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and N-methyl morpholine(NMM). In order to prepare multiply modified alginates, the first stepwas repeated using a different alcohol or amine from Table 4. Alginatesmodified with amine Z2 were then reacted with sodium azide to preparethe corresponding azide-modified alginate. These alginates, along withalginates modified with amine Z1, were then reacted with one of thealkynes listed in Table 4 in the presence of CuSO₄ and sodium ascorbatein order to prepare tetrazole-modified alginates.

Following each covalent modification, the modified alginates werefiltered through a cyano-modified silica column to capture bulk organicimpurities. Finally, after completing all covalent modification steps,the modified alginates were dialyzed against 10,000 MWCO membrane toremove any remaining small-molecule or low molecular weight impurities.

The purity of the modified alginates was determined by ¹H NMR analysis.The ¹H NMR spectra of each modified alginate polymer was collected, andpeaks corresponding to the modified alginate polymer and to anyimpurities were integrated to determine the relative quantity of eachspecies in the sample.

TABLE 4 Chemical modifications of the 73 capsule formulations Alginate #Modifications Alginate # Modifications  1 O1-O7 38 N2-Z2-Y6  2 O3-O10 39N2  3 O1-O11 40 O5-O9  4 O9-O12 41 Z2-Y15  5 O3-O7 42 Z1-Y18  6 Z2-Y8 43O7  7 Z1-Y20 44 Z1-Y12  8 SLG100 45 N9-Z1-Y18  9 Z2-Y16 46 O10 10 Z2-Y1347 Z2-Y7 11 Z2-Y17 48 Z1-Y10 12 O5 49 N6 13 O7-O9 50 Z2-Y13 14 Z2-Y15 51O12 15 O8 52 N3 16 O4-O1 53 O4 17 Z2-Y4 54 Z1-Y11 18 N9-Z1-Y16 55 Z1-Y1719 Z1-Y4 56 Z1-Y1 20 VLVG 57 Z1-Y9 21 Z1-Y6 58 Z2-Y6 22 Z2-Y11 59 SLG2023 N1 60 N5 24 N9 61 Z1-Y3 25 Z2-Y3 62 Z2-Y5 26 N6-Z1-Y18 63 Z1 27 O9-O264 O6 28 Z2-Y2 65 Z1-Y15 29 Z1-Y7 66 Z1-Y2 30 O4-O7 67 N8 31 N4-N2 68Z1-Y19 32 Z1-Y8 69 O3 33 Z2-Y16 70 Z2-Y12 34 V/S 71 N7 35 Z2 72 O9 36Z1-Y14 73 O11 37 O9-O3

A. Chemical Modification of Alginate Curtails the Foreign Body Responsein C57BL/6 mice

The physicochemical parameters governing anti-fibrotic properties arecurrently poorly understood, making rationally designed approacheschallenging (Williams, Biomaterials 29:2941-2953 (2008)). To betterunderstand which structural features are germane to anti-fibroticproperties, a pool of diverse chemical compounds was selected that canmodify latent functionalities and properties on the polymeric alginatebackbone (FIG. 7). A 774-membered alginate analogue library wasconstructed with a variety of amines, alcohols, azides, and alkynes(FIG. 9). Of the 774 alginate analogues, 35 analogues resulted inunacceptably low yields and 634 alginates were determined to be capableof gelation after modification. These alginates were then evaluated asbulk hydrogels in a subcutaneous high-throughput mouse to measure levelsof acute inflammation (Tables 5-9). 200 alginate analogues displayedlower levels of cathepsin activity than the control alginate UPVLVG, thealginate used as the starting material for the library synthesis.Component designations refer to the components of Table 4 and FIG. 7.This assay monitors neutrophil activation subcutaneously with an imagingagent which yields increased fluorescence in response to increasedneutrophil-mediated cathepsin activity. Two hundred analogues displayedfluorescent levels that were lower than the base unmodified, ultrapureVLVG alginate (FIG. 11).

Since microcapsules have been the preferred alginate geometry in bothdrug delivery and cell encapsulation applications, 70 of the top 200performing polymers (Table 4) from the initial screen were fabricatedinto 300 μm capsules and re-evaluated in the subcutaneous inflammationassay (FIG. 12). Using chemically-modified alginate proved problematicin constructing microspheres, and good capsule morphology was restoredby blending a small amount of ultrapure SLG100 alginate with thealginate analogue solution.

TABLE 5 Cathepsin Activity of Singularly Modified Alginate PolymersCathepsin Cathepsin Cathepsin Moiety Activity Moiety Activity MoietyActivity N8 3.69 Z2-Y16 1.37 Z1-Y4 0.48 N9 0.76 Z2-Y10 1.37 Z1-Y6 0.50N3 1.14 Z2-Y14 1.00 Z1-Y17 0.58 N6 1.37 Z2-Y5 1.14 Z1-Y1 0.82 N4 1.37Z2-Y12 0.84 Z1-Y2 0.48 N5 2040 Z2-Y7 1.37 Z1-Y11 0.64 N2 0.96 Z2-Y6 0.71Z1-Y10 0.54 N1 1.57 Z2-Y8 0.97 Z1-Y12 0.84 N7 0.39 Z2-Y20 1.57 Z1-Y130.76 O6 — Z2-Y3 1.37 Z1-Y16 0.92 O12 0.81 Z2-Y18 1.37 Z1-Y9 0.60 O11 —Z2-Y2 2.17 Z1-Y14 0.79 O5 1.17 Z2-Y4 1.60 Z1-Y15 0.82 O3 1.17 Z2-Y171.60 Z1-Y7 0.66 O4 0.96 Z2-Y1 1.77 Z1-Y5 0.42 O9 0.82 Z2-Y11 1.60 Z1-Y200.50 O7 0.72 Z2-Y9 0.8 Z1-Y3 0.42 O8 0.96 Z2-Y13 1.57 Z1-Y18 0.56 O20.97 Z2-Y15 0.91 Z1-Y19 0.54 O1 1.17 Z2-Y19 — Z1-Y8 0.58 O10 0.69

TABLE 6 Cathepsin Activity of Multiply Modified Alginate Polymers N8 N9N3 N6 N4 N5 N2 N1 N7 N7 — — 0.20 — — — — — — N9 0.51 — — — 0.42 0.540.92 — 1.37 N4 1.37 0.48 2.40 — −1.14 — 2.17 0.76 1.17 N2 — 0.81 — —0.86 0.80 −2.40 — — N6 — 0.60 — — — — — 0.91 1.37 N8 0.87 0.97 — — 1.170.86 — 0.97 O3 0.71 0.88 0.60 0.72 0.6 0.58 0.58 0.64 0.76 O2 0.63 0.990.78 0.69 0.91 0.64 0.75 0.72 1.17 O10 1.17 0.72 0.95 0.78 0.92 0.880.82 0.88 0.69 O1 0.97 0.91 0.80 0.76 0.92 0.89 0.88 0.88 0.75 O8 0.870.92 0.81 0.93 0.78 0.80 0.84 0.81 0.89 O12 0.76 0.88 0.79 0.87 0.810.75 0.82 0.75 0.76 O9 0.88 0.92 1.17 0.85 0.84 0.78 1.17 1.17 0.89 O71.17 0.97 0.99 0.96 1.17 1.17 1.17 0.84 1.37 O4 0.89 0.71 1.17 0.78 1.371.14 0.76 0.91 1.60 O5 — 0.88 0.54 0.96 0.96 1.37 0.60 0.69 1.17 O111.00 1.37 — 1.17 — — 0.75 0.69 1.17 N1 2.57 1.77 — 1.17 — 0.56 — −0.501.17 N3 1.37 1.17 −0.82 0.75 — — 1.57 — — N5 0.75 1.60 0.69 1.60 — —0.63 — 0.24 O6 0.75 — 0.63 — 0.69 0.89 0.82 0.81 —

TABLE 7 Cathepsin Activity of Multiply Modified Alginate Polymers N2 N1N3 N4 N5 N7 N9 N8 N6 Z2-Y16 1.14 — 1.17 0.60 0.75 1.17 1.37 1.57 0.93Z2-Y10 — — 1.37 1.37 — 1.17 1.37 1.14 1.37 Z2-Y14 — — — — 1.60 1.97 1.771.77 1.77 Z2-Y5  1.37 1.17 0.96 1.37 0.87 0.93 0.86 0.66 0.66 Z2-Y121.37 1.77 1.37 1.37 1.97 1.17 1.14 0.96 0.88 Z2-Y7  0.75 0.66 0.99 0.760.81 — 0.96 0.79 0.96 Z2-Y6  0.78 1.37 0.97 0.84 0.92 — 0.82 0.54 0.97Z2-Y8  — 1.17 — — 1.37 1.14 1.37 1.37 1.37 Z2-Y20 0.51 1.37 0.56 0.440.58 1.37 1.60 0.46 1.37 Z2-Y3  0.79 1.17 0.69 0.94 0.92 1.57 1.37 1.372.00 Z2-Y18 1.37 0.93 1.37 1.14 1.37 0.82 1.57 1.57 1.37 Z2-Y2  1.370.86 0.82 1.17 1.57 1.37 1.37 1.57 1.60 Z2-Y4  1.14 1.37 1.37 — 1.371.17 1.60 1.60 1.97 Z2-Y17 1.37 — 1.37 1.17 0.94 1.37 1.00 1.17 1.37Z2-Y1  1.17 — 1.37 0.92 — 0.93 0.80 1.37 1.37 Z2-Y11 0.95 1.37 1.37 — —1.37 — — — Z2-Y9  0.72 0.84 0.92 0.69 — 0.75 1.77 1.37 1.37 Z2-Y13 1.371.37 1.60 0.75 1.37 1.37 — 1.57 1.77 Z2-Y15 1.57 1.17 1.00 — — 1.57 — —— Z2-Y19 — — — — — — — — —

TABLE 8 Cathepsin Activity of Multiply Modified Alginate Polymers N1 N4N7 N3 N2 N8 N5 N9 N6 Z1-Y4  0.63 0.51 1.17 0.51 0.60 1.37 1.37 1.37 1.17Z1-Y6  1.17 0.88 1.17 0.84 0.75 0.87 0.75 1.57 0.99 Z1-Y17 0.72 0.780.91 0.58 0.79 0.56 0.76 0.81 0.69 Z1-Y1  0.63 0.58 1.17 0.50 0.54 0.500.50 1.17 1.17 Z1-Y2  1.00 1.37 1.17 1.37 1.37 1.37 1.37 1.37 1.37Z1-Y11 1.00 1.37 1.37 1.37 1.37 1.00 1.17 1.34 1.37 Z1-Y10 1.14 1.001.37 1.37 1.14 1.37 1.37 0.97 1.37 Z1-Y12 1.37 1.17 1.37 1.37 1.37 1.171.37 1.17 1.17 Z1-Y13 1.14 0.99 1.14 1.37 1.17 1.17 1.17 1.17 1.17Z1-Y16 1.37 1.14 1.17 1.37 1.17 1.00 1.17 0.97 0.96 Z1-Y9  0.97 0.940.94 0.97 0.93 0.84 0.96 0.87 0.84 Z1-Y14 0.89 0.99 0.85 0.88 1.17 0.760.78 0.85 0.86 Z1-Y15 0.94 0.92 0.99 0.89 1.17 1.17 1.37 0.89 1.37Z1-Y7  1.37 0.77 1.00 0.76 1.37 0.76 0.75 1.14 1.17 Z1-Y5  1.14 0.991.17 0.96 1.00 1.37 1.57 1.17 1.17 Z1-Y20 0.75 0.84 1.14 0.97 1.14 1.371.17 0.81 0.79 Z1-Y3  1.37 1.17 0.86 1.17 1.37 1.37 0.94 0.58 0.96Z1-Y18 0.75 0.82 — 0.77 — — — 0.63 0.63 Z1-Y19 1.17 — 0.99 — — — — —1.17 Z1-Y8  — 1.17 1.00 0.94 0.92 0.94 1.14 1.37 0.97

TABLE 9 Cathepsin Activity of Multiply Modified Alginate Polymers O6 O12O11 O5 O3 O4 O9 O7 O8 O2 O1 O10 O7 1.37 1.17 — — 1.17 0.99 1.37 1.371.17 1.37 1.37 1.14 O9 1.14 1.37 — — 1.37 1.37 1.17 1.17 1.37 1.14 1.771.14 O1 0.86 0.82 1.37 1.17 1.37 0.92 0.97 0.97 1.37 0.97 1.17 1.17 O21.14 0.97 1.17 1.00 0.95 — 0.89 0.76 0.91 0.76 0.92 0.72 O6 1.37 — — — —0.99 1.37 1.17 0.85 0.79 0.78 1.37 O12 0.99 1.77 0.89 1.37 1.37 1.170.75 0.96 — — — — O3 1.95 1.60 1.37 — — 1.17 0.87 0.80 1.14 — 0.93 0.97O5 — 1.97 — — — 1.00 — — 1.17 — 0.79 0.94 O11 — 1.17 0.95 — — — — — —1.17 1.37 1.14 O4 — 1.37 — — — — — — 0.94 0.92 0.97 1.14 O10 — 1.57 0.880.99 0.96 1.17 — 1.17 — 0.80 1.17 1.37 O8 — 1.57 — 0.71 0.72 0.85 0.800.92 1.37 0.69 1.37 1.14

All modified microcapsule formulations required this blending, capsulesmade from a blended solution of unmodified alginates VLVG and SLG100(V/S) and the conventional SLG20 capsule formulation served as controls.Of the 70 formulated alginate microcapsules, an improved inflammationresponse was observed with several polymers (FIG. 12). The top 10modified microcapsules displayed inflammation levels of 10-40% lowerthan the control alginates. To see if these lower levels of acuteinflammation translated into lower levels of fibrosis, the implant sitesof these top 10 alginates were sampled, sectioned, and processedhistologically after 28 days. Three modified alginates, Z2-Y12, Z1-Y15,and Z1-Y19, displayed minimal fibrotic overgrowth with capsules able tofully detach from the surrounding tissue.

To test if the subcutaneous results translate into other implantationsites, 300 μm capsules of the top 10 lead modified alginates wereimplanted in the intraperitoneal (IP) space of C57BL/6 mice. Capsuleswere retrieved after 14 days and evaluated for the accumulation ofcellular and fibrotic tissue. Phase contrast imaging of retrievedcontrol capsules show a robust fibrotic response, with a white fibrouscollagenous deposition observed on the capsules with brown capsuleclumping. By comparison, the top ten lead modified alginates showvarying degrees of fibrosis, with the modified alginates Z2-Y12, Z1-Y15,and Z1-Y19 showing almost no fibrous deposition and emerging asmaterials with anti-fibrotic properties.

Cellular staining and confocal microscopy of the Z2-Y12, Z1-Y15, andZ1-Y19 capsules showed little to no presence of macrophages (CD68),myofibroblasts (SMA) or general cellular deposition (DAPI). Theconventional microcapsule alginate, however, showed significantquantities of these cell populations on the retrieved capsules. Cellulardeposition is a key mechanistic component of material recognition and aninitiator of collagenous deposition, and the absence of cells on thecapsule surface is a further illustration of the anti-fibroticproperties of these modified alginates. To confirm these results, theSMA levels of Z2-Y12, Z1-Y15, Z1-Y19, and the control capsulesquantified by Western Blotting. 40 different cytokines from proteinsamples extracted from the retrieved microcapsules were also profiled.The cytokine profile of Z2-Y12 microcapsules show the lowest cytokinelevels of all tested samples, indicative of an overall lowerinflammatory response. Importantly, retrieved Z2-Y12 capsules had lowprotein levels of TNF-α, IL-13, IL-6, G-CSF, GM-CSF, IL-4, CCL2, andCCL4 which are known mediators of the foreign body response and fibrosis(Rodriguez et al., J. Biomed. Mater. Res. A 89:152-159 (2009)).Quantification of seventy nine RNA sequences of known inflammationfactors and immune cell markers isolated from retrieved capsules alsosupport lower levels of inflammation for Z2-Y12 implants. The RNAprofile in the surrounding IP fluid and fat tissue of Z2-Y12 implantedmice also more closely resembled mock treatment than mice implanted withcontrol capsules, further demonstrating the lower inflammatory potentialof this material.

B. Anti-Fibrotic Alginates Show Lower Macrophage Adhesion

FACS analysis was performed on retrieved capsules after 14 days IP tocharacterize the different immune populations that are recruited toZ2-Y12 capsules compared to control capsules (FIG. 8). Z2-Y12 capsulesdisplayed significantly lower percentages of macrophage and neutrophilpopulations, suggesting that Z2-Y12 capsules may be interfering witheither the recruitment of immune cell populations or amplification of aninflammatory response. To see if lower macrophage recruitment wasevident in vivo, IP intra-vital imaging was performed 7 days afterimplantation of fluorescent Z2-Y12 capsules in MAFIA mice (wheremacrophages express GFP) and compared them to fluorescent SLG20capsules. SLG20 capsules show a large population of macrophages activelyaggregating at the surface of these capsules, an indication offoreign-body giant cell formation and a clear step towards fibrosis.Z2-Y12 capsules by comparison showed much lower levels of macrophagesnear the capsules and there was no visible macrophage aggregation.

The lack of immune cell recruitment/activation to the surface of Z2-Y12capsules is consistent with the chemical modification of the polymerchains creating differential surfaces. Confocal raman spectroscopicmapping was performed to determine the distribution of the Z2-Y12chemical modification in the microcapsule. Strikingly, the diagnosticraman signature for the tetrahydropyranyl modification had a higherintensity at the surface of the microcapsule than at the core.Freeze-fracture cryo-SEM was then performed on Z2-Y12 microcapsules toexamine both the surface and core topography of the alginate analoguemicrospheres and compare them to the control capsule formulations.Z2-Y12 capsules display a more variable porosity throughout the capsulecore compared to either the blended control or conventional SLG20capsules, with pores ranging from 1 μm to 10 μm in size. The surfacefeatures between the different capsule formulations are quite distinct;the surface of Z2-Y12 capsules show fewer cratered features. Thesesurface differences are likely created by interactions at the boundarylayer between the modified polymer chains and the surrounding aqueoussolution.

C. Z2-Y12, Z1-Y15, and Z1-Y19 Resist Fibrosis in Non-Human Primates

The lead materials, Z2-Y12, Z1-Y15, and Z1-Y19, were advanced intoprimate studies to test their anti-fibrotic properties in a NHP model.Previous reports from our lab have established that spheroid size isalso a key parameter in mitigating fibrosis, with larger spheres (>1 mm)displaying anti-fibrotic properties. 1.5 mm capsules of the conventionalSLG20 capsules and the new Z2-Y12, Z1-Y15, and Z1-Y19 formulatedcapsules were separately transplanted into non-human primates (n=3 each)using a minimally invasive laparoscopic procedure. Capsules wereretrieved by IP lavage at 2 and 4 weeks, with one primate from eachcohort allowed to continue for 6 months. By 14 days post-transplant,SLG201.5 mm capsules were also largely free and not embedded in tissueat 2 weeks as well. However, numerous capsules were fibrosed and clumpedtogether. The 1.5 mm Z2-Y12, Z1-Y15, and Z1-Y19 retained a highretrieval rate and minimal embedding into the surrounding tissue. Atboth 2 and 4 weeks Z2-Y12, Z1-Y15, and Z1-Y19 capsules displayedsignificantly reduced fibrotic responses in phase contrast imagingcompared to 1.5 mm SLG20 capsules. Confocal imaging and FACS analysis ofretrieved capsules showed large 1.5 mm SLG20 capsules had more extensiveimmune macrophage and fibrosis-associated activated myofibroblastcoverage, consistent with the visible fibrotic overgrowth seen in thephase contrast imaging.

To investigate whether increasing capsule size and/or the modifiedchemistries would maintain improved anti-fibrotic activity over a longerperiod of time, confocal staining was also performed on capsulesretrieved from NHPs after 6 months. SLG20 capsules showed significantand extensive fibrotic overgrowth, while Z2-Y12 capsules were stillclean, showing no associated macrophages or myofibroblasts. FACSanalysis displayed similar results with a lower macrophage compositionassociated with retrieved Z2-Y12 capsules.

The combination of both increased capsule size (1.5 mm) and modified(Z2-Y12) chemistry substantially improved biocompatibility even at the 6month time point. Large 1.5 mm Z2-Y12 capsules looked to have minimal(almost non-existent) levels of fibrosis throughout all time points,indicating that anti-fibrotic effects of large capsule size synergizewith those of modified Z2-Y12 chemistry.

The results in this example demonstrate that chemical modification ofone of the most widely used biomaterials, alginate, produces hydrogelsthat are able to resist foreign body reactions in both rodents andnon-human primates. The lead alginate analogues, Z2-Y12, Z1-Y15, andZ1-Y19, show minimal recognition by macrophages and other immune cells,low levels of inflammatory cytokines, and almost no visible fibrousdeposition in both rodents and non-human primates even after 6 months(Z2-Y12). The distribution of the Z2-Y12 chemical modification resultsin a unique hydrogel surface that inhibits macrophage adhesion,effectively mitigating the foreign body response to the biomaterial. Theresults show that chemical modification of existing biomaterials is aviable strategy to overcome their foreign body responses. These are thefirst biomaterials to resist the foreign body response in non-humanprimates and their versatility as alginate-based materials allows itsuse in multiple biomedical applications.

Example 9: Demonstration of Anti-Fibrotic Activity of Modified AlginatesEncapsulating Human Cells in Immunocompetent Animals

This example demonstrates the anti-fibrotic properties of the modifiedalginates encapsulating human cells, which are implanted in robustimmunocompetent STZ C57BL/6J mice for a long period of time. Theencapsulated human cells are actively secreting xenogeneic substancesincluding, but not limited to, proteins. The xenogeneic substancesshould elicit an intense immune response from the mice. Therefore, thistest represents a severe immune challenge to the implanted modifiedalginates. Nonetheless, the implanted modified alginates resist foreignbody responses and shield the encapsulated human cells from host foreignbody responses for long periods of time. As a result, the beneficialeffects of the human cells are exerted for long periods of time. Thisexample describes testing of modified alginates encapsulating humancells secreting insulin for their ability to reduce blood glucose levelsand maintain normoglycemia in STZ-induced diabetic mice. The implantsreduce blood glucose levels and maintain normoglycemia long-term in theSTZ C57BL/6J mice without the need for immune suppressants.

Diabetes is a global epidemic afflicting over 300 million people (Shawet al., Diabetes Res. Clin. Pract. 87:4-14 (2010)). While a rigorousregimen of blood glucose monitoring coupled with daily injections ofexogenous insulin remains the leading treatment for type one diabetics,patients still suffer ill effects due to the challenges associated withdaily compliance (Pickup et al., N. Engl. J. Med. 366:1616-1624 (2012)).In addition, the regulation of insulin secretion by the beta cells ofthe pancreatic islets of Langerhans in response to blood glucose levelis a highly dynamic process, which is imperfectly simulated by periodicinsulin injections (Robertson et al., N. Engl. J. Med. 350:694-705(2004)). The transplantation of donor tissue, either in the form of apancreas transplantation or infusion of cadaveric islets, are currentlyimplemented clinically as one strategy to achieve insulin independencefor type 1 diabetics (Shapiro et al., N. Engl. J. Med. 355:1318-1330(2006); Shapiro et al., N. Engl. J. Med. 343:230-238 (2000); Q₁ et al.,Acta Diabetologica 51:833-843 (2014)). This approach has been limiteddue to two major drawbacks: (1) the limited supply of available donortissue, and (2) the adverse effects associated with a lifetime ofimmunosuppression (Hirshberg et al., Current Diabetes Reports 7:301-303(2007); Gibly et al., Diabetologia, 54:2494-2505 (2011); O'Sullivan etal., Endocrine Reviews 32:827-844 (2011)). Methods to relieve the needfor life long immunosuppression must be developed to allow for thebroadest clinical implementation (Hirshberg et al., Current DiabetesReports 7:301-303 (2007); Shapiro et al., The Review of DiabeticStudies: RDS 9:385-406 (2012); Vogel et al., Diabetologia 56:1605-1614(2013)).

Cell encapsulation is a promising technology that overcomes the need ofimmunosuppression by protecting therapeutic tissues from host rejection(Dolgin, Nat. Med. 20:9-11 (2014); Jacobs-Tulleneers-Thevissen et al.,Diabetologia 56:1605-1614 (2013)). The most commonly investigated methodfor islet encapsulation therapy is the formulation of isolated isletsinto alginate microspheres (Jacobs-Tulleneers-Thevissen et al.,Diabetologia 56:1605-1614 (2013); Scharp et al., Advanced Drug DeliveryReviews 67-68:35-73 (2014)). Clinical evaluation of this technology indiabetic patients with cadaveric human islets has only achieved glycemiccorrection for short periods (Jacobs-Tulleneers-Thevissen et al.,Diabetologia 56:1605-1614 (2013); Basta et al., Diabetes Care34:2406-2409 (2011); Calafiore et al., Diabetes Care 29:137-138,(2006)). Implants from these studies are characterized by strongimmune-mediated foreign body responses that result in fibroticdeposition, nutrient isolation, and donor tissue necrosis (de Groot elal., Journal of Surgical Research 121:141-150 (2004); Tuch et al.,Diabetes Care 32:1887-1889 (2009)). Similar results are observed withencapsulated xenogeneic islets and pancreatic progenitor cells inpreclinical diabetic mouse or non-human primate models, where both thetherapeutic efficacy (Hirshberg et al., Current Diabetes Reports7:301-303 (2007)) of encapsulated cadaveric human islets and pig isletsis hampered by immunological responses (Elliot et al., TransplantationProceedings 37:3505-3508 (2005); Omer et al., Diabetes 52:69-75 (2003);Schneider et al., Diabetes 54:687-693 (2005)).

A major contributor to the performance of encapsulated cell implants isthe immune response to the biomaterials used for cell encapsulation (Limet al., Science 210:908-910 (1980); Jacobs-Tulleneers-Thevissen et al.,Diabetologia 56:1605-1614 (2013); Scharp et al., Advanced Drug DeliveryReviews 67-68:35-73 (2014)). Immune-mediated foreign body responses toimplanted materials commonly lead to tissue capsule formation thatresults in implant failure (King et al., Journal of Biomedical MaterialsResearch 57:374-383 (2001)). When implanted into the intraperitonealspace of non-human primates or rodents with robust immune systems suchas C57BL/6J, (King et al., Journal of Biomedical Materials Research57:374-383 (2001); Dang et al., Biomaterials 32, 4464-4470 (2011))alginate microspheres elicit foreign body reactions and fibrosis (Kinget al., Journal of Biomedical Materials Research 57:374-383 (2001); Danget al., Biomaterials 32:4464-4470 (2011)).

A large library of chemically modified alginates was recently developedand evaluated for their potential to resist implant rejection in bothrodent and non-human primate models. This example extends that work toshow that triazole-thiomorpholine dioxide (TMTD; FIG. 13)alginate-encapsulating human cells were able to mitigate foreign bodyresponses in immune-competent C57BL/6 mice (FIGS. 14 through 16). As aresult, the TMTD alginate-encapsulating human cells are able to providelong-term glycemic correction and glucose-responsiveness. These resultsdemonstrate that these new materials can be used to provide long-term,glycemic correction through implantation of microencapsulated humancell, thus improving therapeutic effect of such implanted cells.

This example demonstrates the successful use potential of encapsulatedhuman cells in immunocompetent animals for the restoration ofnormoglycemia without immune suppression. This shows the expectationthat the disclosed modified alginates can be used to encapsulate cellsand coat material and keep immune reactions to the cells and materialsat bay in subjects in which they are implanted. To ensure properbiocompatibility assessment in these studies an immunocompetentstreptozotocin-induced diabetic C57BL/6 mouse model was used becausethis strain is known to produce a strong fibrotic and foreign bodyresponse similar to observations made in human patients (Kolb et al., J.Respir. Cell. Mol. Biol. 27:141-150 (2002)). Formulations that haveshown glycemic correction utilizing other tissue sources, such asconventional microencapsulation with alginate (Lim et al., Science 210;908-910 (1980); Calafiore el al., Diabetes Care 29:137-138, (2006)) andlarger sphere formulations (Veiseh et al., Nat. Mater., DOI:10.1038/NMAT4290), were unable to support glycemic correction with humancells.

All materials were implanted intraperitoneally and retrieved atspecified times from immunocompetent streptozotocin induced diabeticC57BL/6 or B6.129S6-Ccr6tm1(EGFP)Irw/J mice in accordance with approvedprotocols and federal guidelines. Sample processing, staining, FACS, andimaging were performed as detailed in below.

I. Materials

All chemicals were obtained from Sigma-Aldrich (St. Louis, Mo.) and cellculture reagents from Life Technologies (Grand Island, N.Y.), unlessotherwise noted. Antibodies: Alexa Fluor 488-conjugated anti-mouse CD68(Cat. #137012, Clone FA-11) and Alexa Fluor 647-conjugated anti-mouseLy-6G/Ly-6C (Gr-1) (Cat. #137012, Clone RB6-8C5) were purchased fromBioLegend Inc. (San Diego, Calif.). Cy3-conjugated anti-mouse alphasmooth muscle actin antibody was purchased from Sigma Aldrich (St. LouisMo.). Filamentous actin (F-actin)-specific Alexa Fluor 488-conjugatedPhalloidin was purchased from Life Technologies (Grand Island, N.Y.).Anti-Glucagon cat #ab82270, Anti-insulin cat #ab7842, Goat Anti-Guineapig IgG H&L conjugated Alexa Fluor® 488 cat #ab150185, and GoatAnti-Mouse IgG H&L conjugated Alexa Fluor®594 cat #ab150116 werepurchased from abeam (Cambridge, Mass.). Anti-human C-peptide cat#GN-1D4 was purchased from Developmental Studies Hybridoma Bank(University of Iowa, Iowa City, Iowa). A sampling of the spheres used inthis study was submitted for endotoxin testing by a commercial vendor(Charles River, Wilmington, Mass.) and the results showed that spherescontained <0.05 EU/ml of endotoxin levels.

II. Methods

A. Fabrication of Alginate Hydrogel Capsules and Cell Encapsulation

All buffers were sterilized by autoclave and alginate solutions weresterilized by filtration through a 0.2 um filter. After solutions weresterilized, aseptic processing was implemented by performing capsuleformation in a type II class A2 biosafety cabinet to maintain sterilityof manufactured microcapsules/spheres for subsequent implantation. Thehydrogel capsules following the protocol described in Example 8.

To solubilize alginates, SLG20 (NovaMatrix, Sandvika, Norway) wasdissolved at 1.4% weight to volume in 0.8% saline. TMTD alginate wasinitially dissolved at 5% weight to volume in 0.8% saline, and thenblended with 3% weight to volume SLG100 (also dissolved in 0.8% saline)at a volume ratio of 80% TMTD alginate to 20% SLG100.

For formation of 0.5 mm spheres were generated with a 25G blunt needle,a voltage of 5 kV and a 200 μl/min flow rate. For formation of 1.5 mmspheres, an 18 gauge blunt tipped needle (SAI Infusion Technologies) wasused with a voltage of 5-7 kV.

Cultured human cells were used for encapsulation. Immediately prior toencapsulation, the cultured human cell clusters were centrifuged at1,400 rpm for 1 minute and washed with Ca-free Krebs-Henseleit (KH)Buffer (4.7 mM KCl, 25 mM HEPES, 1.2 mM KH₂PO₄, 1.2 mM MgSO₄×7H₂O, 135mM NaCl, pH≈7.4, ≈290 mOsm). After washing, the human cells werecentrifuged again and all supernatant was aspirated. The human cellpellet was then re-suspended in the SLG20 or TMTD alginate solutions(described above) at cluster densities of 1,000, 250, and 100 clustersper 0.5 ml alginate solution. Spheres were crosslinked using a BaCl₂gelling solution and their sizes were controlled as described above.Immediately after crosslinking, the encapsulated human cell clusterswere washed 4 times with 50 mL of CMRLM media and cultured overnight ina spinner flask at 37° C. prior to transplantation. Due to an inevitableloss of human cell clusters during the encapsulation process, the totalnumber of encapsulated clusters were recounted post-encapsulation.

B. Transplantation Surgeries

All animal protocols were approved by the MIT Committee on Animal Care,and all surgical procedures and post-operative care was supervised byMIT Division of Comparative Medicine veterinary staff. Immune-competentmale STZ-induced diabetic C57BL/6 mice (Jackson Laboratory, Bar Harbor,Me.) or male B6.129S6-Ccr6tml(EGFP)Irw/J mice (Jackson Laboratory, BarHarbor, Me.) were anesthetized with 3% isoflurane in oxygen and hadtheir abdomens shaved and sterilized using betadine and isopropanol.Preoperatively, all mice also received a 0.05 mg/kg dose ofbuprenorphine subcutaneously as a pre-surgical analgesic, along with 0.3mL of 0.9% saline subcutaneously to prevent dehydration. A 0.5 mmincision was made along the midline of the abdomen and the peritoneallining was exposed using blunt dissection. The peritoneal wall was thengrasped with forceps and a 0.5-1 mm incision was made along the lineaalba. A desired volume of spheres (all materials without islets, as wellas SLG20 spheres encapsulating rat islets) were then loaded into asterile pipette and implanted into the peritoneal cavity through theincision. The incision was then closed using 5-0 taper-tippedpolydioxanone (PDS II) absorbable sutures. The skin was then closed overthe incision using a wound clip and tissue glue.

C. Blood Glucose Monitoring

To create insulin-dependent diabetic mice, healthy C57BL/6 mice weretreated with Streptozotocin (STZ) by the vendor (Jackson Laboratory, BarHarbor, Me.) prior to shipment to MIT. The blood glucose levels of allthe mice were retested prior to transplantation. Only mice whosenon-fasted blood glucose levels were above 400 mg/dL for two consecutivedays were considered diabetic and underwent transplantation.

Blood glucose levels were monitored three times a week followingtransplantation of islet-containing alginate capsules. A small drop ofblood was collected from the tail vein using a lancet and tested using acommercial glucometer (Clarity One, Clarity Diagnostic Test Group, BocaRaton, Fla.). Mice with unfasted blood glucose levels below 200 mg/dLwere considered normoglycemic. Monitoring continued until experimentaltime points had been reached, at which point they were euthanized andthe spheres were retrieved.

D. Human c-Peptide Monitoring

Human c-peptide levels were monitored every three weeks followingtransplantation of human cell-containing alginate capsules. Mice werefasted for 1 hour before blood collection, at which point approximately100-150 μL of blood was collected retro-orbitally into a serumcollection tube. Collected blood was centrifuged for 10 minutes at 13000rpm, serum was removed, and stored at 20° C. until assayed. Serum wasassayed for human c-peptide using the Alpco human c-peptide kit (Catalog#: 80-CPTHU-E10) according to the manufacturer's instructions.

E. Retrieval of Cells, Tissues and Materials

Retrieval of cells, tissues and materials was performed as describedabove in Example 8.

F. Imaging of the Retrieved Material Spheres

For phase contrast imaging of retrieved materials was performedfollowing the protocol described in Example 8.

For bright-field imaging of retrieved materials, samples were gentlywashed using Krebs buffer and transferred into 35 mm petri dishes forbright-field imaging using a Leica Stereoscopic microscope.

G. Confocal Immunofluorescence

Immunofluorescence imaging was used to determine immune populationsattached to spheres. Materials were retrieved from mice and fixedovernight using 4% paraformaldehyde at 4° C. Samples were then washedtwice with KREBS buffer, permeabilized for 30 min using a 0.1% TritonX100 solution, and subsequently blocked for 1 hour using a 1% bovineserum albumin (BSA) solution. Next, the spheres were incubated for 1hour in an immunostaining cocktail solution consisting of DAPI (500 nM),specific marker probes (1:200 dilution) in BSA. After staining, sphereswere washed three times with a 0.1% Tween 20 solution and maintained ina 50% glycerol solution. Spheres were then transferred to glass bottomdishes and imaged using an LSM 700 point scanning confocal microscope(Carl Zeiss Microscopy, Jena Germany) equipped with 5 and 10×objectives. Obtained images were adjusted linearly for presentationusing Photoshop (Adobe Inc. Seattle, Wash.).

H. Proteomic Analysis

I. Reduction, Alkylation and Tryptic Digestion

Retrieved samples were suspended in urea cell lysis buffer (8 M urea,Tris pH 8.0) and incubated at 4° C. overnight. Equivalent amounts ofprotein were reduced (10 mM dithiothreitol, 56° C. for 45 min) andalkylated (50 mM iodoacetamide, room temperature in the dark for 1 h).Proteins were subsequently digested with trypsin (sequencing grade,Promega, Madison, Wis.), at an enzyme/substrate ratio of 1:50, at roomtemperature overnight in 100 mM ammonium acetate pH 8.9. Trypsinactivity was quenched by adding formic acid to a final concentration of5%. Peptides were desalted using C18 SpinTips (Protea, Morgantown, W.Va.) then lyophilized and stored at −80° C.

2. TMT Labeling

Peptides were labeled with TMT 6plex (Thermo) per manufacturer'sinstructions. Lyophilized samples were dissolved in 70 μL ethanol and 30μl of 500 mM triethylammonium bicarbonate, pH 8.5, and the TMT reagentwas dissolved in 30 μl of anhydrous acetonitrile. The solutioncontaining peptides and TMT reagent was vortexed, incubated at roomtemperature for 1 h. Samples labeled with the six different isotopic TMTreagents were combined and concentrated to completion in a vacuumcentrifuge. For the first analysis samples were labeled using the TMT6plex channels as follows: 126-RZA 1.5 mm 250 biological replicate 1;127-RZA 1.5 mm 250 biological replicate 2; 128-SLG201.5 mm 250biological replicate 1; 129-SLG201.5 mm 250 biological replicate 2;130-SLG20500 μm 250 biological replicate 1; and 131-SLG20 500 μm 250biological replicate 2. For the second analysis samples were labeledusing the TMT 6plex channels as follows: 126-RZA 1.5 mm 250 biologicalreplicate 3; 127-RZA 1.5 mm 250 biological replicate 4; 128-SLG201.5 mm250 biological replicate 3; 129-SLG201.5 mm 250 biological replicate 4;130-SLG20500 μm 250 biological replicate 3; and 131-SLG20500 μm 250biological replicate 4.

3. LC-MS/MS

Peptides were then loaded on a precolumn and separated by reverse phaseHPLC (Thermo Easy nLC1000) over a 140 minute gradient beforenanoelectrospray using a QExactive mass spectrometer (Thermo). The massspectrometer was operated in a data-dependent mode. The parameters forthe full scan MS were: resolution of 70,000 across 350-2000 m/z, AGC3e⁶, and maximum IT 50 ms. The full MS scan was followed by MS/MS forthe top 10 precursor ions in each cycle with a NCE of 32 and dynamicexclusion of 30 s. Raw mass spectral data files (.raw) were searchedusing Proteome Discoverer (Thermo) and Mascot version 2.4.1 (MatrixScience). Mascot search parameters were: 10 ppm mass tolerance forprecursor ions; 0.8 Da the fragment ion mass tolerance; 2 missedcleavages of trypsin; fixed modification was carbamidomethylation ofcysteine; variable modification was methionine oxidation. TMTquantification was obtained using Proteome Discoverer and isotopicallycorrected per manufacturer's instructions.

I. Histological Processing for H&E and Masson's Trichrome Staining

Retrieved materials were fixed overnight using 4% paraformaldehyde at 4°C. After fixation, alginate sphere or retrieved tissue samples werewashed using 70% alcohol. The materials were then mixed with 4 degreescalcium-cooled Histogel (VWR, CA #60872-486). After the molds hardened,the blocks were processed for paraffin embedding, sectioning andstaining according to standard histological methods.

J. Histological Immunostaining

Paraffin embedded sectioned samples were stained for the following:human insulin (Anti-insulin cat #ab7842, abeam), human c-peptide(C-peptide cat #GN-1D4, Developmental Studies Hybridoma Bank, Universityof Iowa), human glucagon (Anti-Glucagon cat #ab82270, abeam). Cellularnuclei were stained with DAPI (cat #D1306, Life Technologies).

Paraffin slides were deparaffinized through subsequent incubations inthe following solvents (Xylene 5 min 2×100% ETOH 2 min×295% 2 min×270% 2min×2 d-water). Antigen retrieval was done by incubating sections for 30min in ice cooled PBS, and then blocking with 3% horse serum to blockfor 30 min. Antibody mixtures were then applied as follows: PrimaryA—Mix together Glucagon 1 to 200 and c-peptide 1 to 500. Primary B—Mixtogether Human insulin 1 to 500 and glucagon 1 to 200, incubate for 2hours and then Wash in PBS 10 min x 4. Secondary A—Add anti-mouse AF5941to 500 and anti-rat AF4881 to 500. Secondary B—Add anti-guinea pigAF4881 to 500 with anti-mouse AF5941 to 500 incubate for 30 min thenwash 10 min 4×. Slides were then stained with DAPI and coverslipsmounted using prolong gold antifade (Life Technologies, Carlsbad,Calif.).

K. Western Blotting

Protein was extracted directly from materials for western blot analysis.For protein analyses, retrieved materials were prepared by immersingmaterials in Pierce RIPA buffer (Cat. #89901, Thermo Scientific) withprotease inhibitors (Halt Protease inhibitor single-use cocktail, Cat.#78430, Thermo Scientific) on ice, and then lysed by sonication (for 30seconds on, 30 seconds off, twice at 70% amplitude). Samples were thensubjected to constant agitation for 2 hours at 4° C. Lysates were thencentrifuged for 20 min at 12,000 rpm at 4° C., and protein-containingsupernatants were collected in fresh tubes kept on ice. In samples fromfat tissue, an excess of fat (a top layer on the supernatant) was firstremoved before supernatant transfer. 20 μg protein (quantified by BCAassay, Pierce BCA protein assay kit, Cat. #23225, Thermo Scientific) foreach lane was boiled at 95° C. for 5 min and electrophoresed onSDS-polyacrylamide gels (Any kD 15-well comb mini-gel, Biorad, Cat.#456-9036) and then blotted onto nitrocellulose membranes (Biorad, Cat.#162-0213). Blots were probed with anti-αSmooth Muscle actin antibody(1:400 dilution, Rabbit polyclonal to alpha smooth muscle actin; Cat.#ab5694, AbCam), anti-PDX1 antibody (1:1000 dilution, Rabbit polyclonalto pancreatic & duodenal homeobox 1; Cat. #06-1379, EMD Millipore), andanti-β-actin antibody (1:4000 dilution, monoclonal anti-β-actin antibodyproduced in mouse; Cat. #A1978, Sigma Aldrich) as a loading controlfollowed by donkey anti-rabbit (1:15,000 dilution, Cat. #926-32213,Li-Cor) and goat anti-mouse (1:15,000 dilution, Cat. #926-68070, Li-Cor)fluorophore-conjugated secondary antibodies. Antibody-antigen complexeswere visualized using Odyssey detection (Li-Cor, Serial No. ODY-2329) at700 and 800 nm wavelengths.

L. FACS Analysis

Single-cell suspensions of freshly excised tissues were prepared using agentleMACS Dissociator (Miltenyi Biotec, Auburn, Calif.) according tothe manufacturer's protocol. Single-cell suspensions were prepared in apassive PEB dissociation buffer (IX PBS, pH 7.2, 0.5% BSA, and 2 mMEDTA) and suspensions were passed through 70 μm filters (Cat. #22363548,Fisher Scientific, Pittsburgh, Pa.). This process removed the majorityof cells adhered to the surface (>90%). All tissue and materialsample-derived, single-cell populations were then subjected to red bloodcell lysis with 5 ml of IX RBC lysis buffer (Cat. #00-4333, eBioscience,San Diego, Calif., USA) for 5 min at 4° C. The reaction was terminatedby the addition of 20 ml of sterile IX PBS. The cells remaining werecentrifuged at 300-400 g at 4° C., and resuspended in a minimal volume(˜50 μl) of eBioscience Staining Buffer (cat. #00-4222) for antibodyincubation. All samples were then co-stained in the dark for 25 min at4° C. with two of the fluorescently tagged monoclonal antibodiesspecific for the cell markers CD68 (1 μl (0.5 μg) per sample;CD68-Alexa647, Clone FA-11, Cat. #11-5931, BioLegend), Ly-6G (Gr-1) (1μl (0.5 μg) per sample; Ly-6G-Alexa-647, Clone RB6-8C5, Cat. #108418,BioLegend), CD11b (1 μl (0.2 μg) per sample; or CD11b-Alexa-488, CloneM1/70, Cat. #101217, BioLegend), CD19 (1 μl (0.2 μg) per sample;CD19-Alexa-647, Clone HIB19, Cat. #302222, BioLegend), or IgM (1 μl (0.2μg) per sample; IgM-FITC, Clone RMM-1, Cat. #406505, BioLegend), CD8⁺ (1μl (0.2 μg) per sample, BioLegend). Two ml of eBioscience Flow CytometryStaining Buffer (cat. #00-4222, eBioscience) was then added, and thesamples were centrifuged at 400-500 g for 5 min at 4° C. Supernatantswere removed by aspiration, and this wash step was repeated two moretimes with staining buffer. Following the third wash, each sample wasresuspended in 500 μl of Flow Cytometry Staining Buffer and run througha 40 μm filter (Cat. #22363547, Fisher Scientific) for eventual FACSanalysis using a BD FACSCalibur (cat. #342975), BD Biosciences, SanJose, Calif., USA). For proper background and laser intensity settings,unstained, single antibody, and IgG (labeled with either Alexa-488 orAlexa-647, BioLegend) controls were also run.

M. Intravital Imaging

For intravital imaging, human cell-containing hydrogels of 0.5 mm and1.5 mm sizes were fabricated with Qdot 605 (Life technologies, GrandIsland, N.Y.) and surgically implanted intoB6A29S6-Ccr6^(tml<(EGFP)Irw)/J mice as described above.

After 14 days post implantation, the mice were placed under isofluraneanesthesia and a small incision was made at the site of the originalsurgery to expose beads. The mice were placed on an inverted microscopeand imaged using a 25×, N.A. 1.05 objective on an Olympus FVB-1000 MPmultiphoton microscope at an excitation wavelength of 860 nm. Z-stacksof 200 μm (10 μm steps) were acquired at 2-minute intervals for timeseries of 20-45 minutes depending on the image. The mice were kept underconstant isoflurane anesthesia and monitored throughout the imagingsession. Obtained images were analyzed using Velocity 3D Image AnalysisSoftware (Perkin Elmer, Waltham, Mass.).

N. In Vivo Glucose Challenges (GSIS)

Mice were fasted overnight (12 hours) prior to glucose challenge. On theday of the challenge, fasting blood glucose levels were measured andthen mice were injected via tail-vein with a 30 g/L solution of glucoseat a dose of 200 mg/kg. Blood glucose was then monitored every 15minutes for 2 hours.

O. Pancreas Removal and Insulin Quantification

After 174 days, mice treated with human cells encapsulated inTMTD-alginate were euthanized and the pancreas of each mouse removed.Each pancreas was weighed and then placed into vial with a stainlesssteel ball while keeping samples frozen in liquid nitrogen. A volume of3 ml of acid ethanol was added to each vial and samples were homogenizedon a GenoGrinder at 1000 rpm at 1 min increments until tissue waspulverized. Sample vials are held by aluminum blocks that can be placedin liquid nitrogen between each cycle to keep it cold. Vials were thencentrifuged at 2400 rpm at 4° C. for 30 min. The supernatant (nowcontaining insulin) was removed and stored, while the vial is filledwith more acid ethanol and vortexed. The vials were left overnightshaking at 4° C. Again, vials were centrifuged at 2400 rpm at 4° C. for30 min and the supernatant was collected and added to the previouslystored supernatant. Acid ethanol was again added to the vials, vortexed,incubated overnight, centrifuged, and supernatant collected andcombined. Supernatant solution was evaporated using a Genevac EZ-2 plus.Samples were stored at −80° C. until used. Prior to insulinquantification, samples were resuspended in PBS and quantified using amouse insulin ELISA kit (Alpco catalog #: 80-INSMS-E10) according tomanufacturer's instructions. This same procedure was repeated forhealthy, wild type C57BL/6 mice and a STZ treated C57BL/6 mice.

P. Statistical Analysis

Data are expressed as mean±SEM, and N=5 mice per time point and pertreatment group. For Rat studies N=3 per treatment. These sample sizeswere chosen based on previous literature. All animals were included inanalyses except in instances of unforeseen sickness or morbidity. Animalcohorts were randomly selected. Investigators were not blind toperformed experiments. FACS data was analyzed for statisticalsignificance either by unpaired, two-tailed t-test, or one-way ANOVAwith Bonferroni multiple comparison correction, unless indicatedotherwise, as implemented in GraphPad Prism 5; *: p<0.05, **: p<0.001,and ***: p<0.0001.

Quantified data shown are group mean values±SEM.

II. Results

A. TMTD Alginate Mitigates Immunological Responses to Encapsulated HumanCells.

It has been recently demonstrated that microsphere size can have abeneficial impact on resisting immunological responses to implantedalginates, with spheres of 1.5 mm diameters and larger and TMTDalginates, mitigating fibrotic responses in both rodents and non-humanprimates (Veiseh et al. in press and Vegas et al. submitted). Thechemical structure of TMTD is shown in FIG. 13.

To evaluate the immune responses to these spheres, encapsulated humancells were implanted IP into C57BL/6 mice and were retrieved after 14days. Cells associated with the outside of the spheres were isolated andanalyzed by FACS (FIGS. 14 and 15). Statistically significant lowerlevels of macrophages, neutrophils, B cells, and CD8+ T cells weremeasured for TMTD alginate encapsulated human cells (formulation 3)compared to SLG20 controls (formulation 1, 2). Implants retrieved after80-90 days in STZ-C57BL/6J mice revealed that TMTD alginate spheres hadmuch lower levels of fibrotic deposition. Immunofluorescence staining ofthese retrieved spheres for cellular deposition (DAPI, F-actin) andmyofibroblasts (α-SMA) showed significantly lower levels of cellulardeposition on TMTD alginate spheres. Proteomic analysis of these proteinextracts detected 18 collagen isoforms, and 10 out of the 18 detectedcollagen proteins were significantly reduced in TMTD alginatetransplants further showing that these materials are able to mitigatefibrotic responses.

Western blot quantification of α-SMA protein extracted from theretrieved implants is consistent with lower fibrosis levels on TMTDspheres (FIG. 10).

Finally, consistent with these results, histological processing andimmunostaining of TMTD encapsulated human clusters retrieved after over90 days from STZ-C57BL/6 mice revealed cell clusters with positiveco-localized staining of mature human cell markers human insulin andc-peptide. Minimal to no co-localized staining was observed betweenhuman c-peptide and glucagon or human insulin and glucagon, consistentwith the human cells retaining their differentiation state through theentire study.

The ability of TMTD alginate spheres to provide immunoisolation of theencapsulated human cells was next characterized. Freeze-fracturecryogenic scanning electron microscopy (cryo-SEM) of the spheres displaya heterogeneous pore structure with pore sizes ranging from sub-micronto 1-3 μm in size, a range capable of preventing permeation by cells andlarge proteins. Intravital imaging of transplanted spheres after 14 daysin B6A29S6-Ccr6tm1(EGFP)Irw/J mice (where T, B, and dendritic cellsexpress EGFP) showed localization of CCR6+ cells to regions of spherescontaining human cells, but an inability of these cells to make contactand initiate cytotoxic events.

B. Encapsulation of Human Cells with Triazole-Thiomorpholine Dioxide(TMTD) Alginate Enables Glycemic Correction in STZ-C57BL/6J.

To investigate the potential of microencapsulation of human cells toprovide glycemic correction, cells were used in three differentformulations: (1) 500 μm alginate microcapsules conventionally used forislet encapsulation (Lim et al., Science 210:908-910 (1980); Calafioreet al., Diabetes Care 29:137-138 (2006)), (2) 1.5 mm alginate spheres(Veiseh et al. in press), and (3) 1.5 mm TMTD alginate spheres. Each ofthese formulations was transplanted in streptozotocin (STZ) treatedC57BL/6J mice at three different doses of human cell clusters andevaluated for their ability to restore normoglycemia. Naked,non-encapsulated human cells are unable to provide glycemic correctionin this diabetic model regardless of implantation site.

Encapsulation into 500 μm barium alginate microcapsules is a commonlyimplemented formulation for islet transplantation (Lim et al., Science210, 908-910 (1980); Calafiore, et al., Diabetes Care 29:137-138,(2006)). Mice transplanted with human cells encapsulated in 500 μmmicrocapsules showed the lowest levels of glycemic control, with onlythe highest dose of transplanted clusters able to restore normoglycemiafor 15 days. Human cells encapsulated in 1.5 mm alginate spheresperformed better than the 500 μm microcapsule formulation withnormoglycemia maintained for 20-30 days for the two higher doses,consistent with earlier results obtained using rat islets (Veiseh et al.in press). Sustained normoglycemia was achieved for over 70 days with1.5 mm TMTD alginate spheres at all three doses tested. Robust humanc-peptide levels were measured at 21, 43, and 63 days during the courseof this study, consistent with human cell function, with TMTD alginatespheres showing the highest levels of human c-peptide.

C. Encapsulated Human Cells Support Sustained Normoglycemia and GlucoseResponsiveness in STZ-C57BL/6J.

To evaluate the capacity of TMTD alginate encapsulated human celltransplants to sustain normoglycemia, a cohort of transplanted diabeticmice was tracked for 6 months. Transplanted mice successfully maintainedglycemic correction over the 6-month period, and 5 closely matched theblood glucose levels of wild type C57BL/6J mice tracked over a similarperiod. In addition, robust human c-peptide levels over 100 pmol/L wererecorded at multiple points throughout the study. A glucose challengewas also performed on these mice 150 days post-transplantation, andencapsulated human cells restored normoglycemia comparably to wild typemice. Host pancreas insulin levels for each cohort were also analyzed toconfirm the successful STZ treatment and a lack of endogenous pancreascell regeneration. Human cells implants retrieved after 6 monthsdisplayed no signs of fibrotic overgrowth, with little collagenous andcellular deposition evident on the capsule. Since spheres retrievedafter 3 months showed minimal levels of fibrosis, this indicates thatTMTD alginate mitigates immunological responses by altering the immunerecognition/activation kinetics.

The results show that encapsulated human cells can achieveglucose-responsive, long-term glycemic correction (over 170 days) in animmune-competent diabetic animal with no immunosuppression. This resultwas accomplished by implementing a novel TMTD alginate formulation thatmitigates immunological responses to human cell implants, effectivelydelaying the fibrotic deposition that leads to implant tissue necrosis.This formulation provided sufficient immunoprotection to enablelong-term glycemic correction, in spite of the xenogeneic stimulationthat these human cells manifest in an immunocompetent rodent recipient.These result support the expectation that human cells encapsulated inthe disclosed modified alginates can provide insulin independence forpatients suffering from type 1 diabetes. These result support theexpectation that human cells encapsulated in the disclosed modifiedalginates can provide products produced by the encapsulated cells topatients for long periods of time.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of skill in the artto which the disclosed invention belongs. Publications cited herein andthe materials for which they are cited are specifically incorporated byreference.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

1.-32. (canceled)
 33. A composition comprising a preparation of alginatecapsules encapsulating mammalian cells, wherein at least 95% of thecapsules in the preparation have a diameter between 1 mm and 4 mm,inclusive, wherein the capsules comprise a singularly modified alginatepolymer comprising one or more covalently modified monomers defined byFormula I

wherein —X—R₁ is selected from the group consisting of:


34. The composition of claim 33, wherein —X—R₁ is


35. The composition of claim 33, wherein the cells comprise stem cells,cells derived from stem cells, cells from a cell line, primary cells,reprogrammed cells, reprogrammed stem cells, cells derived fromreprogrammed stem cells, or genetically engineered cells.
 36. Thecomposition of claim 33, wherein the cells are neural cells, ganglioncells, retinal epithelial cells, adrenal medulla cells, lung cells,cardiac muscle cells, osteoclast cells, bone marrow cells, spleen cells,thymus cells, glandular cells, blood cells, myogenic cells,keratinocytes, or smooth muscle cells.
 37. The composition of claim 33,wherein the cells secrete a therapeutically effective substance.
 38. Thecomposition of claim 33, wherein at least 95% of the capsules in thepreparation have a diameter of 1 mm to 2 mm, inclusive.
 39. Thecomposition of claim 38, wherein the modified alginate polymer iscrosslinked ionically.
 40. The composition of claim 38, wherein thecapsules further comprise an unmodified alginate.
 41. The composition ofclaim 40, wherein at least 95% of the capsules in the preparation have asphere or sphere-like shape.
 42. The composition of claim 41, whereinthe cells are genetically engineered to produce a protein or nucleicacid.
 43. The composition of claim 42, wherein the protein is a hormone,a growth factor, or an enzyme.
 44. The composition of claim 42, whereinthe protein is an antigen or an antibody.
 45. The composition of claim42, wherein the protein is a tumor antigen.
 46. The composition of claim42, wherein the protein comprises the antigen binding domain of anantibody.
 47. The composition of claim 42, wherein the protein is ablood clotting factor.
 48. The composition of claim 42, wherein theprotein is an enzyme useful to treat a lysosomal storage disorder. 49.The composition of claim 48, wherein the enzyme is selected from thegroup consisting of cerebrosidase, beta-hexosaminidase A,alpha-galactosidase, alpha-iduronidase, iduronate sulfatase, an enzymeinvolved in heparan sulfate degradation, arylsulfatase B, galactose6-sulfatase, and beta-galactosidase.
 50. A method of treating a diseaseor disorder in a human patient, comprising implanting or transplantinginto the human patient a composition according to claim
 33. 51. Themethod of claim 50, wherein the disease is diabetes and the mammaliancells are insulin-producing cells derived from reprogrammed stem cells.52. The method of claim 50, wherein the disease is hemophilia and themammalian cells are genetically engineered to produce a blood clottingfactor.
 53. The method of claim 50, wherein the disease is Fabry diseaseand the cells are genetically engineered to produce alpha-galactosidase.54. The method of claim 50, wherein the disease is Hurler syndrome andthe cells are genetically engineered to produce alpha-iduronidase.